Unravelling the Paradoxical Effects of Ganglia Ablation Benjamin J. Scherlag and Warren M. Jackman Circ Arrhythm Electrophysiol. 2014;7:570-572 doi: 10.1161/CIRCEP.114.001908 Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3149. Online ISSN: 1941-3084
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circep.ahajournals.org/content/7/4/570
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Arrhythmia and Electrophysiology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Arrhythmia and Electrophysiology is online at: http://circep.ahajournals.org//subscriptions/
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Editorial Unravelling the Paradoxical Effects of Ganglia Ablation Benjamin J. Scherlag, PhD; Warren M. Jackman, MD
I
n 1973, Lazzara et al1 described 2 clusters of nerve bodies called ganglionated plexi (GP) adjacent to the sinus node and AV junction; high-frequency electric stimulation, which did not excite the underlying atrium, induced heart rate or AV conduction slowing, respectively. We are indebted to Randall et al2 who spent the next several decades delineating the anatomy and physiology of the intrinsic cardiac autonomic nervous system consisting of GP located at several sites in the atria and ventricles. Carrying on the legacy of Dr Randall,2 Armour and Ardell3,4 produced numerous publications and books, providing a hierarchical construct of the neural innervation of the heart, starting at the nuclei and axonal fields in the brain (extrinsic autonomic nervous system) followed by the spinal cord (intrathoracic) ganglia and axons and their connections to the intrinsic cardiac autonomic system with its GP and their axons of passage. The last part of this interconnected chain (the atrial neural network) was delineated anatomically by Armour et al5 and Pauza et al6 and functionally by Hou et al.7
Article see p 711 The overall function of the intrinsic autonomic nervous system consisting of the GP and the atrial neural network was summarized by Ardell,8 “… the intrinsic cardiac nerve plexus (GP and neural network) acts as more than a simple relay station for extrinsic autonomic projections to the heart…modulating…extrinsic and local cardio-cardiac reflexes. The intrinsic cardiac nerve plexus contains a heterogeneous population of cell types, including parasympathetic and sympathetic efferent neurons as well as afferent neurons.” Furthermore, as pointed out by Ardell,8 these afferent neurons participate in reflex loops between and within the various levels of the extrinsic, intrathoracic, and intrinsic systems, yet each level when disconnected from the other would retain independent functionality. From 1997 to 1998, the seminal studies by Jaïs et al9 and Haïssaguerre et al10 showed that the myocardium of the pulmonary veins (PVs) manifested ectopic firing in patients, and this ectopy was directly associated with the initiation and maintenance of atrial fibrillation (AF). As a result, the accepted catheter ablation procedure for AF became isolation of the PVs. These findings engendered basic experimental studies demonstrating that chemical stimulation11 of the GP at the atrial The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City. Correspondence to Benjamin J. Scherlag, PhD, Heart Rhythm Institute, Oklahoma University Health Sciences Center, 1200 Everett Dr, 6E-103, Oklahoma City, OK 73104. E-mail [email protected] (Circ Arrhythm Electrophysiol. 2014;7:570-572.) © 2014 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.114.001908
PV entrances or electric stimulation of the nerves within the PV could induce PV firing and AF.12 Moreover, these studies specifically implicated the excessive release of both the cholinergic (marked shortening of the refractory period) and the adrenergic (induction of triggered firing) neurotransmitters as the mechanism for PV firing and ensuing AF. Clinical studies,13,14 including surgical approaches,15,16 have provided evidence that ablation of GP is an important adjunctive procedure to PV isolation in the treatment of AF. These clinical and recent experimental studies have provided enlightening insights into how the autonomic nervous system interacts in the normal and pathological heart to induce and or suppress AF. For example, high-level electric stimulation via the vagal trunks (which markedly slows the heart rate) has been used for >100 years to induce AF acutely in experimental animals. Schauerte et al17 showed that ablating the GP located on the main right pulmonary artery running underneath the aorta and the superior vena cava to the right lung (GP) could suppress the AF induced by vagal stimulation. In regard to chronic forms of AF, Allessie and his associates found that pacing induced AF for weeks provided a chronic model of sustained AF in goats.18 In a series of studies from our laboratory, we found that low level vagal nerve stimulation (at a voltage 50% lower than that which slows the heart rate) paradoxically suppresses or even prevents pacing induced AF19,20 by diminishing both the frequency and amplitude of GP firing.21 Another recent paradoxical finding was a study by Lo et al.21 in which they ablated the superior vena cava-aorta GP, which has been described as the head stage or nexus point GP,22 connecting the extrinsic and the intrinsic autonomic nervous systems. During a period of 10 weeks, the operated animals progressively developed atrial tachycardia/AF, whereas the sham controls did not. This unexpected paradoxical finding was explained based on the inhibitory control normally imposed by the extrinsic on the intrinsic autonomic nervous system. With the disconnect the intrinsic system is now freed to act independently (as alluded to by Ardell8) and achieve a hyperactive state of the intrinsic GP leading to atrial tachycardia/AF. In this issue of the journal, Mao et al23 have reported another example of the apparently paradoxical interaction between the cardiac autonomic nervous system and AF. In a group of dogs, the major 4 GP and ligament of Marshall were ablated, whereas a comparably sized second group served as sham controls (no GP ablation). In the ablated group, the acute studies showed a significant prolongation of effective refractory period (ERP) (atrial refractoriness) and a significant decrease in AF inducibility when compared with baseline values. Eight weeks after ablation the ERP was significantly shorter and AF inducibility was significantly greater than the Sham control group. The authors offer several explanations for their findings, including incomplete denervation and neural GP bypasses both parasympathetic, which would shorten ERP, and sympathetic,
Downloaded from http://circep.ahajournals.org/ at Virginia 570 Commonwealth University on November 2, 2014
Scherlag and Jackman Paradoxical Effects of Ganglia Ablation 571 which would enhance triggered firing by programmed stimulation. As support for this hypothesis of increased sympathetic and parasympathetic innervation, several ancillary findings are cited by the authors, specifically, the heart rate at 8 weeks was significantly higher in the experimental group when compared with that in the sham group. Furthermore, immunohistological studies showed a higher cholinergic and sympathetic nerve density in the experimental but not in the sham group. Moreover, they recognized that the third tier of the cardiac autonomic innervation, the atrial neural network (see above) could serve as the substrate for these proarrhythmic effects. It is interesting to note that in a previous acute study,24 after inducing the same GP and ligament of Marshall ablation, it was shown that the atrial neural network was easily made proarrhythmic by the application of acetylcholine. Indeed, the same concentrations of acetylcholine applied over a small area of the atrial neural network resulted in a significantly shorter induced AF duration than when applied over a larger area of the atrial free wall and appendages. However, what remains to be addressed is the mechanism(s), during the 8-week period, which provided the changes in atrial refractoriness and AF inducibility. The authors refer to their finding that atrial natriuretic peptide levels were increased, which could be a potential contributor for the 8-week findings in the experimental group. An intriguing clue for a neural mechanism to explain the paradox may be from the recent and past studies about blood pressure, a commonly found comorbidity with AF. Renal artery denervation has recently been touted as an effective means for reducing resistant hypertension in patients.25 Of interest, the suggested mechanism is that the ablation of the hyperactive afferent nerves from the renal arteries reduce the abnormal neural input to the medullary centers that control blood pressure in the brain. During a period of time (like the blanking period in AF ablation), there is a reverse remodeling of medullary activity allowing a reduction of the sympathetic outflow, thereby reducing the abnormal vasoconstriction of the renal vessels.26 Could the same medullary centers play a role, albeit in inducing paradoxical hypertension, when normal neural inputs, providing homeostatic control of blood pressure, are ablated? In this regard, Pardo and Vidrio27 in 1964 showed that daily dosing of mecamylamine, a ganglionic blocker, in normal dogs, for a period of several months paradoxically induced a sympathetic form of hypertension. They proposed that the acute effect of a ganglionic blocker that is known to manifest hypotension acutely, in the chronic setting could result from increased vasomotor activity via a feedback mechanism or reflex loop. In the study by Mao et al,23 the paradoxical difference between the acute and the chronic findings for atrial refractoriness and AF inducibility might reside in a similar feedback loop involving a loss of the afferent input from the GP to the vasomotor centers in the brain. During a period of time those medullary nuclei, in response to the decreased neural traffic, adjust by increasing sympathetic and parasympathetic outflow back to the intact atrial neural network. It is interesting to note that a significant increase in the heart rate was noted in the chronic dog studies by Pardo and Vidrio27 as in the present report by Mao et al.23
The present authors clearly recognize that differences exist between their findings on the GP ablation in the experimental setting and when GP ablation is performed in patients particularly when combined with PV isolation as stated in the Limitations section. It seems possible that circumferential ablation of the PV can act to dissect the afferent and efferent portions of the reflex loop described above and thereby further increase the success rate for catheter ablation combining PV isolation and GP ablation when compared with GP ablation alone.14 We think that Mao et al23 by presenting the apparently conflicting findings between the acute and the chronic effects of GP ablation have helped us understand the intricate and interconnected nature of the autonomic nervous system as it applies to the normal heart and to the hearts afflicted with the most common form of clinical arrhythmia, AF.
Disclosures Dr Jackman: Consultant for Biosense Webster, Boston Scientific, VytronUS, and ACT; and Lecture Honoraria from Biosense Webster, Boston Scientific, Biotronik, and AtriCure Dr Scherlag reports no conflicts.
References 1. Lazzara R, Scherlag BJ, Robinson MJ, Samet P. Selective parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circ Res. 1973;32:383–401. 2. Randall WC, ed. Neural Regulation of the Heart. New York, NY: Oxford University Press; 1977. 3. Armour JA, Ardell JL, eds. Neurocardiology. New York, NY: Oxford University Press; 1994. 4. Armour JA, Ardell JL, eds. Basic and Clinical Neurocardiology. New York, NY: Oxford University Press; 2004. 5. Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289–298. 6. Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec. 2000;259:353–382. 7. Hou Y, Scherlag BJ, Lin J, Zhou J, Song J, Zhang Y, Patterson E, Lazzara R, Jackman WM, Po SS. Interactive atrial neural network: determining the connections between ganglionated plexi. Heart Rhythm. 2007;4:56–63. 8. Ardell JL. Structure and function of the mammalian intrinsic cardiac neurons, Chapter 5. In: Armour JA, Ardell JL, eds. Neurocardiology. New York, NY: Oxford University Press; 1994. 9. Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clémenty J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95:572–576. 10. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666. 11. Po SS, Scherlag BJ, Yamanashi WS, Edwards J, Zhou J, Wu R, Geng N, Lazzara R, Jackman WM. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm. 2006;3:201–208. 12. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2:624–631. 13. Scherlag BJ, Nakagawa H, Jackman WM, Yamanashi WS, Patterson E, Po S, Lazzara R. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol. 2005;13(suppl 1):37–42. 14. Katritsis DG, Pokushalov E, Romanov A, Giazitzoglou E, Siontis GC, Po SS, Camm AJ, Ioannidis JP. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol. 2013;62:2318–2325.
Downloaded from http://circep.ahajournals.org/ at Virginia Commonwealth University on November 2, 2014
572 Circ Arrhythm Electrophysiol August 2014 15. Onorati F, Curcio A, Santarpino G, Torella D, Mastroroberto P, Tucci L, Indolfi C, Renzulli A. Routine ganglionic plexi ablation during Maze procedure improves hospital and early follow-up results of mitral surgery. J Thorac Cardiovasc Surg. 2008;136:408–418. 16. Doll N, Pritzwald-Stegmann P, Czesla M, Kempfert J, Stenzel MA, Borger MA, Mohr FW. Ablation of ganglionic plexi during combined surgery for atrial fibrillation. Ann Thorac Surg. 2008;86:1659–1663. 17. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000;102:2774–2780. 18. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968. 19. Li S, Scherlag BJ, Yu L, et al. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2:645–651. 20. Sheng X, Scherlag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol. 2011;57:563–571. 21. Yu L, Scherlag BJ, Li S, et al. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol. 2011;22:455–463.
22. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad. Circulation. 1997;95:2573–2584. 23. Mao J, Yin X, Zhang Y, Yan Q, Dong J, Ma C, Liu X. Ablation of epicardial ganglionated plexi increases atrial vulnerability to arrhythmias in dogs. Circ Arrhythm Electrophysiol. 2014;7:711–717. 24. Mao J, Scherlag BJ, Liu Y, Fan Y, Varma V, Stavrakis S, Po SS. The atrial neural network as a substrate for atrial fibrillation. J Interv Card Electrophysiol. 2012;35:3–9. 25. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–1281. 26. Schlaich MP, Hering D, Sobotka PA, Krum H, Esler MD. Renal denervation in human hypertension: mechanisms, current findings, and future prospects. Curr Hypertens Rep. 2012;14:247–253. 27. Pardo EG, Vidrio H. Sustained hypertension in dogs following chronic administration of ganglionic blocking agents. J Pharmacol Exp Ther. 1964;144:124–130. Key Words: Editorials ◼ atrial fibrillation ◼ autonomic nervous system ◼ ganglionated plexi
Downloaded from http://circep.ahajournals.org/ at Virginia Commonwealth University on November 2, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circep.ahajournals.org/content/7/4/570
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Arrhythmia and Electrophysiology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Arrhythmia and Electrophysiology is online at: http://circep.ahajournals.org//subscriptions/
Downloaded from http://circep.ahajournals.org/ at Virginia Commonwealth University on November 2, 2014
Editorial Unravelling the Paradoxical Effects of Ganglia Ablation Benjamin J. Scherlag, PhD; Warren M. Jackman, MD
I
n 1973, Lazzara et al1 described 2 clusters of nerve bodies called ganglionated plexi (GP) adjacent to the sinus node and AV junction; high-frequency electric stimulation, which did not excite the underlying atrium, induced heart rate or AV conduction slowing, respectively. We are indebted to Randall et al2 who spent the next several decades delineating the anatomy and physiology of the intrinsic cardiac autonomic nervous system consisting of GP located at several sites in the atria and ventricles. Carrying on the legacy of Dr Randall,2 Armour and Ardell3,4 produced numerous publications and books, providing a hierarchical construct of the neural innervation of the heart, starting at the nuclei and axonal fields in the brain (extrinsic autonomic nervous system) followed by the spinal cord (intrathoracic) ganglia and axons and their connections to the intrinsic cardiac autonomic system with its GP and their axons of passage. The last part of this interconnected chain (the atrial neural network) was delineated anatomically by Armour et al5 and Pauza et al6 and functionally by Hou et al.7
Article see p 711 The overall function of the intrinsic autonomic nervous system consisting of the GP and the atrial neural network was summarized by Ardell,8 “… the intrinsic cardiac nerve plexus (GP and neural network) acts as more than a simple relay station for extrinsic autonomic projections to the heart…modulating…extrinsic and local cardio-cardiac reflexes. The intrinsic cardiac nerve plexus contains a heterogeneous population of cell types, including parasympathetic and sympathetic efferent neurons as well as afferent neurons.” Furthermore, as pointed out by Ardell,8 these afferent neurons participate in reflex loops between and within the various levels of the extrinsic, intrathoracic, and intrinsic systems, yet each level when disconnected from the other would retain independent functionality. From 1997 to 1998, the seminal studies by Jaïs et al9 and Haïssaguerre et al10 showed that the myocardium of the pulmonary veins (PVs) manifested ectopic firing in patients, and this ectopy was directly associated with the initiation and maintenance of atrial fibrillation (AF). As a result, the accepted catheter ablation procedure for AF became isolation of the PVs. These findings engendered basic experimental studies demonstrating that chemical stimulation11 of the GP at the atrial The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City. Correspondence to Benjamin J. Scherlag, PhD, Heart Rhythm Institute, Oklahoma University Health Sciences Center, 1200 Everett Dr, 6E-103, Oklahoma City, OK 73104. E-mail [email protected] (Circ Arrhythm Electrophysiol. 2014;7:570-572.) © 2014 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.114.001908
PV entrances or electric stimulation of the nerves within the PV could induce PV firing and AF.12 Moreover, these studies specifically implicated the excessive release of both the cholinergic (marked shortening of the refractory period) and the adrenergic (induction of triggered firing) neurotransmitters as the mechanism for PV firing and ensuing AF. Clinical studies,13,14 including surgical approaches,15,16 have provided evidence that ablation of GP is an important adjunctive procedure to PV isolation in the treatment of AF. These clinical and recent experimental studies have provided enlightening insights into how the autonomic nervous system interacts in the normal and pathological heart to induce and or suppress AF. For example, high-level electric stimulation via the vagal trunks (which markedly slows the heart rate) has been used for >100 years to induce AF acutely in experimental animals. Schauerte et al17 showed that ablating the GP located on the main right pulmonary artery running underneath the aorta and the superior vena cava to the right lung (GP) could suppress the AF induced by vagal stimulation. In regard to chronic forms of AF, Allessie and his associates found that pacing induced AF for weeks provided a chronic model of sustained AF in goats.18 In a series of studies from our laboratory, we found that low level vagal nerve stimulation (at a voltage 50% lower than that which slows the heart rate) paradoxically suppresses or even prevents pacing induced AF19,20 by diminishing both the frequency and amplitude of GP firing.21 Another recent paradoxical finding was a study by Lo et al.21 in which they ablated the superior vena cava-aorta GP, which has been described as the head stage or nexus point GP,22 connecting the extrinsic and the intrinsic autonomic nervous systems. During a period of 10 weeks, the operated animals progressively developed atrial tachycardia/AF, whereas the sham controls did not. This unexpected paradoxical finding was explained based on the inhibitory control normally imposed by the extrinsic on the intrinsic autonomic nervous system. With the disconnect the intrinsic system is now freed to act independently (as alluded to by Ardell8) and achieve a hyperactive state of the intrinsic GP leading to atrial tachycardia/AF. In this issue of the journal, Mao et al23 have reported another example of the apparently paradoxical interaction between the cardiac autonomic nervous system and AF. In a group of dogs, the major 4 GP and ligament of Marshall were ablated, whereas a comparably sized second group served as sham controls (no GP ablation). In the ablated group, the acute studies showed a significant prolongation of effective refractory period (ERP) (atrial refractoriness) and a significant decrease in AF inducibility when compared with baseline values. Eight weeks after ablation the ERP was significantly shorter and AF inducibility was significantly greater than the Sham control group. The authors offer several explanations for their findings, including incomplete denervation and neural GP bypasses both parasympathetic, which would shorten ERP, and sympathetic,
Downloaded from http://circep.ahajournals.org/ at Virginia 570 Commonwealth University on November 2, 2014
Scherlag and Jackman Paradoxical Effects of Ganglia Ablation 571 which would enhance triggered firing by programmed stimulation. As support for this hypothesis of increased sympathetic and parasympathetic innervation, several ancillary findings are cited by the authors, specifically, the heart rate at 8 weeks was significantly higher in the experimental group when compared with that in the sham group. Furthermore, immunohistological studies showed a higher cholinergic and sympathetic nerve density in the experimental but not in the sham group. Moreover, they recognized that the third tier of the cardiac autonomic innervation, the atrial neural network (see above) could serve as the substrate for these proarrhythmic effects. It is interesting to note that in a previous acute study,24 after inducing the same GP and ligament of Marshall ablation, it was shown that the atrial neural network was easily made proarrhythmic by the application of acetylcholine. Indeed, the same concentrations of acetylcholine applied over a small area of the atrial neural network resulted in a significantly shorter induced AF duration than when applied over a larger area of the atrial free wall and appendages. However, what remains to be addressed is the mechanism(s), during the 8-week period, which provided the changes in atrial refractoriness and AF inducibility. The authors refer to their finding that atrial natriuretic peptide levels were increased, which could be a potential contributor for the 8-week findings in the experimental group. An intriguing clue for a neural mechanism to explain the paradox may be from the recent and past studies about blood pressure, a commonly found comorbidity with AF. Renal artery denervation has recently been touted as an effective means for reducing resistant hypertension in patients.25 Of interest, the suggested mechanism is that the ablation of the hyperactive afferent nerves from the renal arteries reduce the abnormal neural input to the medullary centers that control blood pressure in the brain. During a period of time (like the blanking period in AF ablation), there is a reverse remodeling of medullary activity allowing a reduction of the sympathetic outflow, thereby reducing the abnormal vasoconstriction of the renal vessels.26 Could the same medullary centers play a role, albeit in inducing paradoxical hypertension, when normal neural inputs, providing homeostatic control of blood pressure, are ablated? In this regard, Pardo and Vidrio27 in 1964 showed that daily dosing of mecamylamine, a ganglionic blocker, in normal dogs, for a period of several months paradoxically induced a sympathetic form of hypertension. They proposed that the acute effect of a ganglionic blocker that is known to manifest hypotension acutely, in the chronic setting could result from increased vasomotor activity via a feedback mechanism or reflex loop. In the study by Mao et al,23 the paradoxical difference between the acute and the chronic findings for atrial refractoriness and AF inducibility might reside in a similar feedback loop involving a loss of the afferent input from the GP to the vasomotor centers in the brain. During a period of time those medullary nuclei, in response to the decreased neural traffic, adjust by increasing sympathetic and parasympathetic outflow back to the intact atrial neural network. It is interesting to note that a significant increase in the heart rate was noted in the chronic dog studies by Pardo and Vidrio27 as in the present report by Mao et al.23
The present authors clearly recognize that differences exist between their findings on the GP ablation in the experimental setting and when GP ablation is performed in patients particularly when combined with PV isolation as stated in the Limitations section. It seems possible that circumferential ablation of the PV can act to dissect the afferent and efferent portions of the reflex loop described above and thereby further increase the success rate for catheter ablation combining PV isolation and GP ablation when compared with GP ablation alone.14 We think that Mao et al23 by presenting the apparently conflicting findings between the acute and the chronic effects of GP ablation have helped us understand the intricate and interconnected nature of the autonomic nervous system as it applies to the normal heart and to the hearts afflicted with the most common form of clinical arrhythmia, AF.
Disclosures Dr Jackman: Consultant for Biosense Webster, Boston Scientific, VytronUS, and ACT; and Lecture Honoraria from Biosense Webster, Boston Scientific, Biotronik, and AtriCure Dr Scherlag reports no conflicts.
References 1. Lazzara R, Scherlag BJ, Robinson MJ, Samet P. Selective parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circ Res. 1973;32:383–401. 2. Randall WC, ed. Neural Regulation of the Heart. New York, NY: Oxford University Press; 1977. 3. Armour JA, Ardell JL, eds. Neurocardiology. New York, NY: Oxford University Press; 1994. 4. Armour JA, Ardell JL, eds. Basic and Clinical Neurocardiology. New York, NY: Oxford University Press; 2004. 5. Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289–298. 6. Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec. 2000;259:353–382. 7. Hou Y, Scherlag BJ, Lin J, Zhou J, Song J, Zhang Y, Patterson E, Lazzara R, Jackman WM, Po SS. Interactive atrial neural network: determining the connections between ganglionated plexi. Heart Rhythm. 2007;4:56–63. 8. Ardell JL. Structure and function of the mammalian intrinsic cardiac neurons, Chapter 5. In: Armour JA, Ardell JL, eds. Neurocardiology. New York, NY: Oxford University Press; 1994. 9. Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clémenty J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95:572–576. 10. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666. 11. Po SS, Scherlag BJ, Yamanashi WS, Edwards J, Zhou J, Wu R, Geng N, Lazzara R, Jackman WM. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm. 2006;3:201–208. 12. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2:624–631. 13. Scherlag BJ, Nakagawa H, Jackman WM, Yamanashi WS, Patterson E, Po S, Lazzara R. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol. 2005;13(suppl 1):37–42. 14. Katritsis DG, Pokushalov E, Romanov A, Giazitzoglou E, Siontis GC, Po SS, Camm AJ, Ioannidis JP. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol. 2013;62:2318–2325.
Downloaded from http://circep.ahajournals.org/ at Virginia Commonwealth University on November 2, 2014
572 Circ Arrhythm Electrophysiol August 2014 15. Onorati F, Curcio A, Santarpino G, Torella D, Mastroroberto P, Tucci L, Indolfi C, Renzulli A. Routine ganglionic plexi ablation during Maze procedure improves hospital and early follow-up results of mitral surgery. J Thorac Cardiovasc Surg. 2008;136:408–418. 16. Doll N, Pritzwald-Stegmann P, Czesla M, Kempfert J, Stenzel MA, Borger MA, Mohr FW. Ablation of ganglionic plexi during combined surgery for atrial fibrillation. Ann Thorac Surg. 2008;86:1659–1663. 17. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000;102:2774–2780. 18. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968. 19. Li S, Scherlag BJ, Yu L, et al. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2:645–651. 20. Sheng X, Scherlag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol. 2011;57:563–571. 21. Yu L, Scherlag BJ, Li S, et al. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol. 2011;22:455–463.
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