Intrinsic cardiac nervous system

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The Intrinsic cardiac nervous system (ICNS), also known as the heart's "little brain," is a complex network of neurons and ganglia embedded within the heart tissue that regulates cardiac function independently of the central nervous system. It modulates heart rate, conduction, and cardiac contractility in response to local and external stimuli. [1] [2] It forms part of the autonomic nervous system.

Contents

Anatomy

The ICNS consists of clusters of neurons, or ganglia, primarily located in the atrial and ventricular walls, with higher concentrations in the sinoatrial (SA) and atrioventricular (AV) nodes. [1] [3] These ganglia contain: [1] [4]

The distribution of ganglia varies across species, with larger mammals (e.g., humans, dogs) having more extensive networks than smaller mammals (e.g., mice, rats). [1]

Cholinergic neurons throughout the GPs project to all areas of the heart, [9] The GP are embedded in the epicardial fat pads, consisting of only a few neurons or as many as 400 neurons. [8]

Post ganglionic neurons from the vagal nerve pathways are components of the Ligament of Marshall, forming part of the "intrinsic" heart nervous system. [10]

There are intrinsic plexi that form part of the autonomic nervous system (ANS), [11] the best known intrinsic plexus being the enteric nervous system. The GP are part of the cardiac intrinsic ANS. [12]

In humans, the ganglia are mostly associated with the posterior or superior aspect of the atria. [13] The ganglia mediate at least some of the effects of vagal nerve stimulation on the sinoatrial node, although don't seem to mediate atrioventricular node conduction. [14]

Development

The ICNS originates from neural crest cells (NCCs) during embryonic development: [1]

Function

The ICNS integrates sensory information from the heart and coordinates local reflexes. [1] Key functions include: [1] [5]

The ICNS interacts with the autonomic nervous system (ANS), receiving input from sympathetic and parasympathetic pathways, but can operate autonomously during disruptions, such as in heart transplants. [1]

Physiology

ICNS neurons release neurotransmitters like acetylcholine, norepinephrine, and neuropeptides (e.g., substance P, neuropeptide Y, vasoactive intestinal peptide (VIP)). [1] [15] These mediate local signaling and modulate ion channels in cardiac cells, affecting cardiac action potentials and contractility. The system exhibits plasticity, adapting to chronic conditions like heart failure or hypertension. [1] [16]

Vagus nerve stimulation has been shown to inhibit the activity of the GP, possibly through nerves that express Nav1.8 (a sodium channel subtype that is necessary for action potentials in these nerves), [17] but combining GP ablation with pulonary vein isolation may be a superior option. [18]

In animal models, cardiac overload leads to change in the electrophysiological properties of these neurons, leading to the suggestion that such changes might be relevant to the pathophysiology of heart failure. [19]

Clinical significance

Dysfunction in the ICNS is implicated in arrhythmias (atrial fibrillation), sick sinus syndrome, heart failure, and sudden cardiac death. Its role in denervated hearts (e.g., post-transplant) highlights its capacity for independent function. Research explores ICNS-targeted therapies, such as neuromodulation, to treat cardiac disorders. [1]

GP are spatially close to the pulmonary veins, so pulmonary vein isolation necessarily affects the GP. [20] [21] GP has been shown to be a contributor to atrial fibrillation (AFib), such that ablation of the GP has been a strategy for treatment of AFib. [8] GP ablation alone has been shown to eliminate AFib in approximately three-quarter of AFib patients. [8]

Ligation of the left atrial appendage may reduce AFib by alteration of the GP. [22]

History

The ICNS was first described in the 19th century through histological studies of cardiac tissue. Advances in electrophysiology and imaging in the 20th century elucidated its functional role. [1] [23]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Fedele, Laura; Brand, Thomas (2020-11-24). "The Intrinsic Cardiac Nervous System and Its Role in Cardiac Pacemaking and Conduction". Journal of Cardiovascular Development and Disease. 7 (4): 54. doi: 10.3390/jcdd7040054 . ISSN   2308-3425. PMC   7712215 . PMID   33255284.
  2. ↑ ARMOUR, J. ANDREW (February 2007). "The little brain on the heart" (PDF). CLEVELAND CLINIC JOURNAL OF MEDICINE.
  3. ↑ Armour, J. Andrew (May 2011). "Physiology of the intrinsic cardiac nervous system" . Heart Rhythm. 8 (5): 739. doi:10.1016/j.hrthm.2011.01.033. PMID   21277999.
  4. ↑ Armour, J. Andrew (1991). "Intrinsic Cardiac Neurons" . Journal of Cardiovascular Electrophysiology. 2 (4): 331–341. doi:10.1111/j.1540-8167.1991.tb01330.x. ISSN   1540-8167.
  5. 1 2 Giannino, Giuseppe; Braia, Valentina; Griffith Brookles, Carola; Giacobbe, Federico; D'Ascenzo, Fabrizio; Angelini, Filippo; Saglietto, Andrea; De Ferrari, Gaetano Maria; Dusi, Veronica (2024-02-07). "The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications". Biology. 13 (2): 105. doi: 10.3390/biology13020105 . ISSN   2079-7737. PMC   10887082 . PMID   38392323.
  6. ↑ Aksu, Tolga; Gupta, Dhiraj; Pauza, Dainius H. (April 2021). "Anatomy and Physiology of Intrinsic Cardiac Autonomic Nervous System". JACC: Case Reports. 3 (4): 625–629. doi:10.1016/j.jaccas.2021.02.018. PMC   8302792 . PMID   34317590.
  7. ↑ Hou, Yinglong; Scherlag, Benjamin J.; Lin, Jiaxiong; Zhou, Jing; Song, Jianguo; Zhang, Ying; Patterson, Eugene; Lazzara, Ralph; Jackman, Warren M.; Po, Sunny S. (2007-01-01). "Interactive atrial neural network: Determining the connections between ganglionated plexi". Heart Rhythm. 4 (1): 56–63. doi:10.1016/j.hrthm.2006.09.020. ISSN   1547-5271. PMID   17198991.
  8. 1 2 3 4 Stavrakis S, Po S (2017). "Ganglionated Plexi Ablation: Physiology and Clinical Applications". Arrhythmia & Electrophysiology Review. 6 (4): 186–190. doi:10.15420/aer2017.26.1. PMC   5739885 . PMID   29326833.
  9. ↑ Ardell JL, Armour JA (2016). "Neurocardiology: Structure-Based Function". Comprehensive Physiology . 6 (4): 1635–1653. doi:10.1002/cphy.c150046. ISBN   978-0-470-65071-4. PMID   27783854.
  10. ↑ Corradi D, Callegari S, Macchi E (2016). "Morphology and pathophysiology of target anatomical sites for ablation procedures in patients with atrial fibrillation: part II: pulmonary veins, caval veins, ganglionated plexi, and ligament of Marshall". International Journal of Cardiology . 168 (3): 1769–1778. doi:10.1016/j.ijcard.2013.06.141. PMID   23907042.
  11. ↑ Wake, Emily; Brack, Kieran (August 2016). "Characterization of the intrinsic cardiac nervous system". Autonomic Neuroscience. 199: 3–16. doi:10.1016/j.autneu.2016.08.006. PMID   27568996.
  12. ↑ Calkins H, Hindricks G, Yamane T (2018). "2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation". Europace . 20 (1): e1 –e160. doi:10.1093/europace/eux274. PMC   5834122 . PMID   29016840.
  13. ↑ Smith, R. B. (January 1971). "The occurrence and location of intrinsic cardiac ganglia and nerve plexuses in the human neonate". The Anatomical Record. 169 (1): 33–40. doi:10.1002/ar.1091690104. PMID   5543924.
  14. ↑ Aksu, Tolga; Gopinathannair, Rakesh; Gupta, Dhiraj; Pauza, Dainius H. (June 2021). "Intrinsic cardiac autonomic nervous system: What do clinical electrophysiologists need to know about the "heart brain"?". Journal of Cardiovascular Electrophysiology. 32 (6): 1737–1747. doi:10.1111/jce.15058. PMID   33928710.
  15. ↑ Lizot, Guénaëlle; Pasqualin, Côme; Tissot, Audrey; Pagès, Stephane; Faivre, Jean-François; Chatelier, Aurélien (2022-08-01). "Molecular and functional characterization of the mouse intrinsic cardiac nervous system". Heart Rhythm. 19 (8): 1352–1362. doi: 10.1016/j.hrthm.2022.04.012 . ISSN   1547-5271. PMID   35447308.
  16. ↑ Giannino, Giuseppe; Braia, Valentina; Griffith Brookles, Carola; Giacobbe, Federico; D’Ascenzo, Fabrizio; Angelini, Filippo; Saglietto, Andrea; De Ferrari, Gaetano Maria; Dusi, Veronica (2024-02-07). "The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications". Biology. 13 (2): 105. doi: 10.3390/biology13020105 . ISSN   2079-7737. PMC   10887082 . PMID   38392323.
  17. ↑ Capilupi MJ, Kerath SM, Becker LB (2020). "Vagus Nerve Stimulation and the Cardiovascular System". Cold Spring Harbor Perspectives in Medicine . 10 (2) a034173. doi: 10.1101/cshperspect.a034173 . PMC   6996447 . PMID   31109966.
  18. ↑ Aksu T, Skeete JR, Huang HH (2022). "Ganglionic Plexus Ablation: A Step-by-step Guide for Electrophysiologists and Review of Modalities for Neuromodulation for the Management of Atrial Fibrillation". Arrhythmia & Electrophysiology Review. 12 e02. doi: 10.15420/aer.2022.37 . PMC   9945432 . PMID   36845167.
  19. ↑ Hardwick, Jean C.; Baran, Caitlin N.; Southerland, E. Marie; Ardell, Jeffrey L. (September 2009). "Remodeling of the guinea pig intrinsic cardiac plexus with chronic pressure overload". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 297 (3): R859 –R866. doi:10.1152/ajpregu.00245.2009. PMC   2739792 . PMID   19605763.
  20. ↑ SHu F, Zheng L, Yao Y (2019). "Avoidance of Vagal Response During Circumferential Pulmonary Vein Isolation: Effect of Initiating Isolation From Right Anterior Ganglionated Plexi". Circulation: Arrhythmia and Electrophysiology. 12 (12) e007811. doi:10.1161/CIRCEP.119.007811. PMID   31760820.
  21. ↑ Zheng S, Zeng Y, Meng X (2014). "Active ganglionated plexi is a predictor of atrial fibrillation recurrence after minimally invasive surgical ablation". Journal of Cardiac Surgery . 29 (2): 279–285. doi: 10.1111/jocs.12299 . PMID   24517359.
  22. ↑ AlTurki A, Huynh T, Essebag V (2018). "Left atrial appendage isolation in atrial fibrillation catheter ablation: A meta-analysis". Journal of Arrhythmia. 34 (5): 478–484. doi:10.1002/joa3.12095. PMC   6174377 . PMID   30327692.
  23. ↑ Herring, Neil; Paterson, David J. (2021-04-30). "The Heart's Little Brain: Shedding New Light and CLARITY on the "Black Box"". Circulation Research. 128 (9): 1297–1299. doi:10.1161/CIRCRESAHA.121.319148. ISSN   1524-4571. PMC   7610721 . PMID   33914607.
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