Nerve Growth Factor Mediates the Vious Cycle between Hyperactivity of Ganglionated Plexus and Atrial Fibrillation
Received Date: May 01, 2018 / Accepted Date: May 10, 2018 / Published Date: May 18, 2018
Ganglionated Plexus (GP) is a complex neural network composed by intrinsic cardiac autonomic nervous system (ANS) and is mainly located in fat pads around the antrum of the pulmonary veins (PVs). Recent studies demonstrated hyperactivity of GPs and atrial fibrillation (AF) formed a vicious cycle, to be specific, hyperactivity of the cardiac GPs facilitated the initiation and maintenance of AF and the activity of cardiac GPs increased as AF continued. In addition, research has confirmed that the Nav1.8 channel is highly expressed in GPs and is closely related to activity of GPs and the inducibility of AF. Nerve growth factor (NGF) is an important neurotrophic factor and the expression of NGF in GPs is up-regulated during AF over time, which could trigger the release of SP in the heart via TRPV1 signaling pathways. Besides, SP could rapidly increase the activity of the Nav1.8 channel, demonstrating the increment of Sensory nerve action potentials. Therefore, we hypothesized that up-regulated NGF during AF could increase the activity of GPs through TRPV1-SP-Nav1.8 channel pathways and contributes to stability of AF. If this hypothesis is proved to be correct, future studies based on this link may help to find new therapeutic targets for the treatment of AF.
Keywords: Ganglionated Plexus; Atrial fibrillation; Nerve growth factor; Nav1.8 channel; TRPV1 receptor
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and the prevalence of AF is expected to increase dramatically over the next few decades . Although AF itself is not typically lethal, it is associated with an increased risk of stroke, heart failure, and dementia, as well as cardiovascular-related and all-cause mortality . In addition, AF accounts for more than one-third of all arrhythmiarelated hospitalizations . Once AF is initiated, it is inclined to sustain itself and cause changes in progressive electrical remodeling  and structural remodeling  of the atria and that promote the occurrence and maintenance of AF, knowing as the concept of “AF begets AF”. Recent years, emerging evidence indicated that autonomic remodeling has a close link with the initiation and maintenance of AF .
The Relationship between Atrial Neural Hyperactivity and AF Inducibility
Cardiac autonomic nerve is made up of two main components: the extrinsic and intrinsic autonomic nervous system (ANS). The former consists mainly of ganglia and their axons located outside the heart and the latter is composed mainly of ganglionated plexi and their axons, which are typically embedded in the epicardial fat pads . As to human hearts, there are at least 7 GP and 4 major left atrial GP are located around the antrum of the PVs . In addition, most of intrinsic cardiac neurons in GPs were found to be cholinergic.
Recently, Several lines of evidence suggested that autonomic remodeling plays an important role in the pathogenesis of AF, which mainly demonstrated as the hyperactivity of the cardiac autonomic nervous system (ANS) [6,9,10] and sympathetic hyperinnervation  and changes of several protein such as nerve growth factor (NGF), small conductance calcium-activated potassium channel type 2 (SK2), neurturin (NRTN) [12,13], to be specific, researchers found that both of extrinsic cardiac nerve activity (ECNA) and intrinsic cardiac nerve activity (ICNA) increased as AF continued. Moreover, in a canine model, researchers found that Stimulation of either the Aortic Root GP or anterior right ganglionated plexuses (GP) could trigger the initiation of AF [14,15]. On the contrary, several studies found that 1) destruction of epicardial fat pads by radiofrequency ablation or surgical excision [16,17], 2) blockade of autonomic nerve within GPs could induced a progressive increase in the AF threshold and prevented the initiation and maintenance of AF . Taken together, these facts confirmed that hyperactivity of the cardiac ANS and AF formed a vicious cycle and suppressed the activity of GPs could effective inhibit the inducibility of AF.
The Expression of NGF within Gps Up-Regulated as AF Continued
NGF is one of the most extensively studied neurotrophic factors, which can be synthesized by several types of cells, including lymphocytes, fibroblasts, macrophages and mast cells , and it is vital for the survival, differentiation, and synaptic activity of the sympathetic and sensory nervous systems [20,21]. There is considerable evidence that the expression of NGF became increasingly up-regulated throughout the progress of AF [12,13], high-frequency electrical field stimulation (HFES) of both parasympathetic  and sympatheticneurons in vitro to mimic rapid atrial depolarization further indicated that the cardiac autonomic neurons are an important source of NGF. Besides, abundant studies have shown that NGF plays an essential role in hyperalgesia and inflammatory pain , which are mainly associated with Nav1.8 channels  and TRPV1 receptors . To be specific, acute exposure of NGF can enhance the activity of TRPV1 receptor within half an hour through phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways  and subsequently trigger the release of SP, which could rapidly potentiates Nav1.8 sodium current via PKCε-dependent signaling pathway . On the other hand, chronic exposure of NGF has been shown to lead to an increase in the expression level of the Nav1.8 channel via transcriptional modification mechanisms [23,28].
Nav1.8 Channel, TRPV1 Receptor and SP are Co-Expressed in Cardiac Vagal Neurons within Gps
Nav1.8 (encoded by SCN10A) is a TTX-R Na+ channel , which is localized predominantly in small/medium nociceptive C/Aδ-type dorsal root ganglia (DRG) neurons , and plays a critical role in the upstroke of action potential in neurons. Recent studies showed that the Nav1.8 channel rather than other types of Voltage-gated sodium channels (VGSCs) is highly expressed within GPs [29,30]. Besides, blockade of the Nav1.8 channel by its special chemical antagonists A803467 could significantly inhibit the activity of GPs [31,32] and counteract the cholinergic effects of GPs stimulation, indicating that the Nav1.8 channel is highly expressed in cardiac vagal neurons and is closely related to the activity of GPs.
The capsaicin receptor TRPV1 (transient receptor potentialvanilloid-1, previously known as vanilloid receptor subtype 1) is a nonselective cation channel, which can be activated by physical and chemical mediators including noxious heat, protons, vanilloid compounds . In recent studies, it has been confirmed that TRPV1 receptors are expressed in cardiac afferent neurons in the nodose ganglia (NG). Besides, Immunocytochemistry further revealed that Substance P (SP), as a member of tachykinin family, also expressed in the cardiac vagal afferent neurons in the NG , it was reported that during ischemia/reperfusion injury, TRPV1 receptors played an important role in mediating cardiac ischemic preconditioning via increasing endogenous SP and led to improved cardiac performance in the diabetic heart [35,36]. In addition, it has reported that SP could activate NK-1 receptor and potentiate Nav1.8 sodium current via PKCε-dependent signaling pathway .
Considering the background above, we hypothesized that NGF was a crucial factor contributing to the vicious cycle between GPs hyperactivity and AF. This hypothesis is supported by three main lines of evidence. First, in a model of AF, direct neural recordings of the activity of GPs increased as AF progressed [12,37], which in turn maintained short and dispersed atrial effective refractory periods to sustain AF. On the contrary, inhibition of the activity of GPs by physical or chemical methods can potently suppress the initiation and maintenance of AF. Second, there is considerable evidence that the expression of NGF became increasingly up-regulated throughout the progress of AF and cells experiment further confirmed that cardiac autonomic nerve is an important resource of NGF. Third, Immunocytochemistry revealed that TRPV1 channel, SP and the Nav1.8 channel definitely expressed in the cardiac vagal afferent neurons, and NGF can not only rapidly enhance the activity of Nav1.8 channel through stimulation of TRPV1 receptor but also increase the expression of Nav1.8 channel.
In summary, the expression of NGF up-regulated as AF continued and induced the hyperactivity of GPs through TRPV1-SP-Nav1.8 channel pathways. The resulting hyperactivity of GPs and AF form a vicious cycle and reciprocally enhance each other.
Evaluation and Discussion of the Hypothesis
To test our hypothesis, several mongrel dogs will be enrolled and Experiments will follow the guidelines outlined by the Care and Use of Laboratory Animals of the National Institutes of Health. First, heart needs to be exprosured by means of thoracotomy and neurons within GPs need to be isolated, the expression of TPRV1 receptor, SP and Nav1.8 channel should be tested by western blot and Quantitative RT-PCR to verify they are indeed co-expressed within GPs. Second, the activity of GPs needs to be recorded by BL-420E multi-lead physiological recorder in baseline and in the present of NGF with or not K252a (a high-affinity nerve growth factor receptor blocker)  respectively. The location of GPs can be confirmed by high frequency stimulation (HFS; 20 Hz, 10– 150 V, 1–10 ms pulse width) where GPs are presumed to be located. As most of intrinsic cardiac neurons in GPs were found to be cholinergic, HFS will induce a significant parasympathetic response, when mean R-R interval demonstrate as ≥ 50% increase, this location is assigned as a GP site . Furthermore, atrial effective refractory period, and the cumulative window of vulnerability should be tested to verify the relationship between the activity of GPs and the inducibility of AF.
The second step is to confirm the mechanism that why NGF can induce the hyperactivity of GPs, in order to answer this question, we will apply an antagonist or agonist to inhibit or mimic the biological effect of NGF, TRPV1 receptor, SP respectively to examine their influence on the activity of GPs and the inducibility of AF, the methods above can refer to these articles [27,31,32,40].
We predict that the Nav1.8 channel, TRPV1, SP are indeed expressed within GPs, and up-regulated NGF within GPs promotes activity of GPs through TRPV1 receptor-SP-Nav1.8 channel pathways and leads to the vicious cycle between GPs hyperactivity and AF.
Underlying Clinical Perspective
Atrial fibrillation (AF) is a complex arrhythmia, although intensive research has been done to try to uncover the riddle, the underlying molecular basis remains only partially understood, we hope that this proposed research will contribute to the greater general knowledge on the mechanism of AF development and break the vicious cycle of “AF Begets AF” by early autonomic intervention. Besides, if this hypothesis proven to be true, it would be beneficial to explain the link between obesity and AF , especially in patients with a higher volume of epicardial adipose tissue [42-44]. As research has revealed that obesity with an expansion of adipose tissue mass can result in the excessive secretion of tumor necrosis factor-alpha, which could induce the expression of NGF . Therefore, this hypothesis is significative, it may help to elucidate the vicious cycle between autonomic remodeling and AF and to find new therapeutic targets for the treatment of AF.
Conflict of Interest Statement
This study was supported by projects of National Natural Science Fund of China (grant number: 81500248, 81570292).
- Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, et al. (2006) Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114: 119-125.
- Heidenreich PA, Solis P, Mark Estes NA, Fonarow GC, Jurgens CY, et al. (2016) 2016 ACC/AHA Clinical performance and quality measures for adults with atrial fibrillation or atrial flutter: A report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. Circ Cardiovasc Qual Outcomes 68: 525-568.
- Ruskin JN, Singh JP (2004) Atrial fibrillation endpoints: Hospitalization. Heart Rhythm 1: 31-35.
- Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, et al. (1999) Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res 44: 121-131.
- Tan TC, Koutsogeorgis ID, Grapsa J, Papadopoulos C, Katsivas A, et al. (2014) Left atrium and the imaging of atrial fibrosis: Catch it if you can! Eur J Clin Invest 44: 872-881.
- Zhang L, Po SS, Wang H, Scherlag BJ, Li H, et al. (2015) Autonomic remodeling: How atrial fibrillation begets atrial fibrillation in the first 24 hours. J Cardiovasc Pharmacol 66: 307-315.
- Hou Y, Scherlag BJ, Lin J, Zhou J, Song J, et al. (2007) Interactive atrial neural network: Determining the connections between ganglionated plexi. Heart Rhythm 4: 56-63.
- Hoover DB, Isaacs ER, Jacques F, Hoard JL, Pagé P, et al. (2009) Localization of multiple neurotransmitters in surgically derived specimens of human atrial ganglia. Neuroscience 164: 1170-1179.
- Tan AY, Zhou S, Ogawa M, Song J, Chu M, et al. (2008) Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 118: 916-925.
- Huang CX, Zhao QY, Jiang H, Li JJ, Yang B (2003) Experimental study of the effect of the vagus nerve on atrial electrical remodeling. Journal of Electrocardiology 36: 295-300.
- Chang CM, Wu TJ, Zhou S, Doshi RN, Lee MH, et al. (2001) Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation 103: 22-25.
- Wang S, Zhou X, Huang B, Wang Z, Zhou L, et al. (2016) Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling. Heart Rhythm 13: 274-281.
- Lu Y, Sun J, Zhou X, Zhang L, Ma M, et al. (2016) Effect of low-level vagus nerve stimulation on cardiac remodeling in a rapid atrial pacing-induced canine model of atrial fibrillation. J Cardiovasc Pharmacol 67: 218-224.
- Wu L, Lu Z, Jiang H, He B, He W, et al. (2012) Low-level ganglionated plexus stimulation facilitates atrial fibrillation: In vivo and in vitro studies. Auton Neurosci 168: 58-65.
- Wang HT, Li ZL, Fan BY, Su FF, Zhao JB, et al. (2014) The independent role of the aortic root ganglionated plexi in the initiation of atrial fibrillation: An experimental study. J Thorac Cardiovasc Surg 148: 73-76.
- Hou Y, Scherlag BJ, Lin J, Zhang Y, Lu Z, et al. (2007) Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: Effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation. J Am Coll Cardiol 50: 61-68.
- Badhwar N, Tschopp DR, Lee RJ (2015) Surgical and concomitant epicardial-endocardial (hybrid) ablation of persistent and long-standing persistent atrial fibrillation. Curr Probl Cardiol 40: 245-267.
- Lu Z, Scherlag BJ, Lin J, Niu G, Fung KM, et al. (2008) Atrial fibrillation begets atrial fibrillation: Autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 1: 184-192.
- Welker P, Grabbe J, Grützkau A, Henz BM (1998) Effects of nerve growth factor (NGF) and other fibroblast-derived growth factors on immature human mast cells (HMC-1). Immunology 94: 310-317.
- Antonucci MT, Bonofiglio R, Papalia T, Caruso F, Caroleo MC, et al. (2009) Nerve growth factor and its monocyte receptors are affected in kidney disease. Nephron Clin Pract 111: c21-c28.
- Saygili E, Schauerte P, Kuppers F, Heck L, Weis J, et al. (2010) Electrical stimulation of sympathetic neurons induces autocrine/paracrine effects of NGF mediated by TrkA. J Mol Cell Cardiol 49: 79-87.
- Rana, OR, Saygili E, Gemein C, Zink MDH, Buhr A, et al. (2011) Chronic electrical neuronal stimulation increases cardiac parasympathetic tone by eliciting neurotrophic effects novelty and SIgnificance. Circ Res 108: 1209-1219.
- Lei S, Dryden WF, Smith PA (2001) Nerve growth factor regulates sodium but not potassium channel currents in sympathetic B neurons of adult bullfrogs. J Neurophysiol 86: 641-650.
- John VH, Main MJ, Powell AJ, Gladwell ZM, Hick C, et al. (2004) Heterologous expression and functional analysis of rat Nav1. 8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23. Neuropharmacology 2004 46: 425-438.
- Shields SD, Ahn HS, Yang Y, Han C, Seal RP, et al. (2012) Nav1. 8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain 153: 2017-2030.
- Zhu W, Oxford GS (2007) Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1. Mol Cell Neurosci 34: 689-700.
- Cang CL, Zhang H, Zhang YQ, Zhao ZQ (2009) PKCε-dependent potentiation of TTX-resistant Na v 1.8 current by neurokinin-1 receptor activation in rat dorsal root ganglion neurons. Mol Pain 5: 33.
- Dib-Hajj SD, Black JA, Cummins TR, Kenney AM, Kocsis JD, et al. (1998) Rescue of α-SNS sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo. J Neurophysiol 79: 2668-2676.
- Facer P, Punjabi PP, Abrari A, Kaba RA, Severs NJ, et al. (2011) Localisation of SCN10A gene product Nav1. 8 and novel pain-related ion channels in human heart. Int Heart J 52: 146-152.
- Verkerk AO, Remme CA, Schumacher CA, Scicluna BP, Wolswinkel R, et al. (2012) Functional NaV1. 8 channels in intracardiac neurons novelty and significance: The link between SCN10A and cardiac electrophysiology. Circ Res 111: 333-343.
- Chen X, Yu L, Shi S, Jiang H, Huan, C, et al. (2016) Neuronal Nav1. 8 channels as a novel therapeutic target of acute atrial fibrillation prevention. J Am Heart Assoc 5: e004050.
- Qi B, Wei Y, Chen S, Zhou G, Li H, et al. (2014) Nav1. 8 channels in ganglionated plexi modulate atrial fibrillation inducibility. Cardiovasc Res 102: 480-486.
- Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, et al. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816-824.
- Ide R, Saiki C, Makino M, Matsumoto S (2012) TRPV1 receptor expression in cardiac vagal afferent neurons of infant rats. Neurosci Lett 507: 67-71.
- Zhong B, Wang DH (2007) TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol 293: H1791-H1798.
- Zheng LR, Zhang YY, Han J, Sun ZW, Zhou SX, et al. (2015) Nerve growth factor rescues diabetic mice heart after ischemia/reperfusion injury via up-regulation of the TRPV1 receptor. J Diabetes Complications 29: 323-328.
- Yu L, Scherlag BJ, Sha Y, Li S, Sharma T, et al. (2012) Interactions between atrial electrical remodeling and autonomic remodeling: How to break the vicious cycle. Heart Rhythm 9: 804-809.
- Raychaudhuri SP, Sanyal M, Weltman H, Kundu-Raychaudhuri S (2004) K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: An in vivo study using the severe combined immunodeficient mouse-human skin model. J Invest Dermatol 122: 812-819.
- Po SS, Nakagawa H, Jackman WM (2009) Localization of left atrial ganglionated plexi in patients with atrial fibrillation. J Cardiovasc Electrophysiol 20: 1186-1189.
- Eskander MA, Ruparel S, Green DP, Chen PB, Por ED, et al. (2015) Persistent nociception triggered by nerve growth factor (NGF) is mediated by TRPV1 and oxidative mechanisms. J Neurosci 35: 8593-8603.
- McCully BH, Hasan W, Streiff CT, Houle JC, Woodward WR, et al. (2013) Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias. Am J Physiol Heart Circ Physiol 305: H1530-H1537.
- Hatem SN, Sanders P (2014) Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res 102: 205-213.
- Liu T, Li G (2011) Periatrial epicardial fat, local pro-and anti-inflammatory balance, and atrial fibrillation. J Am Coll Cardiol 57: 1249.
- Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK (2004) Insulin stimulates interleukin-6 and tumor necrosis factor-α gene expression in human subcutaneous adipose tissue. Am J Physiol Endocrinol Metab 286: E234-E238.
- Wang B, Jenkins JR, Trayhurn P (2005) Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: Integrated response to TNF-alpha. Am J Physiol Endocrinol Metab 288: E731-740
Citation: Cai LD, Liu SW (2018) Nerve Growth Factor Mediates the Vious Cycle between Hyperactivity of Ganglionated Plexus and Atrial Fibrillation. Clin Pharmacol Biopharm 7: 183. DOI: 10.4172/2167-065X.1000183
Copyright: © 2018 Cai LD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
- Total views: 706
- [From(publication date): 0-2018 - Dec 19, 2018]
- Breakdown by view type
- HTML page views: 676
- PDF downloads: 30