Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Jan 1.
Published in final edited form as: Heart Rhythm. 2015 Aug 14;13(1):282–288. doi: 10.1016/j.hrthm.2015.08.022

TARGETED STELLATE DECENTRALIZATION: IMPLICATIONS FOR SYMPATHETIC CONTROL OF VENTRICULAR ELECTROPHYSIOLOGY

Una Buckley 1, Kentaro Yamakawa 1, Tatsuo Takamiya 1, J Andrew Armour 1, Kalyanam Shivkumar 1, Jeffrey L Ardell 1
PMCID: PMC4698240  NIHMSID: NIHMS727244  PMID: 26282244

Abstract

Background

Selective, bilateral cervicothoracic sympathectomy has proven to be effective for managing ventricular arrhythmias in the setting of structural heart disease. The procedure currently employed removes the caudal portions of both stellate ganglia, along with thoracic chain ganglia down to T4 ganglia.

Objective

To define the relative contributions of T1-T2 and the T3-T4 paravertebral ganglia in modulating ventricular electrical function.

Methods

In anesthetized vagotomised porcine subjects (n=8), the heart was exposed via sternotomy along with right and left paravertebral sympathetic ganglia to the T4 level. A 56-electrode epicardial sock was placed over both ventricles to assess epicardial activation recovery intervals (ARI) in response to individually stimulating right and left stellate vs T3 paravertebral ganglia. Responses to T3 stimuli were repeated following surgical removal of the caudal portions of stellate ganglia and T2 bilaterally.

Results

In intact preparations, stellate ganglion vs T3 stimuli (4Hz, 4ms duration) were titrated to produce equivalent decreases in global ventricular ARIs (right-side 85±6 vs 55±10 ms; left-side 24±3 vs 17±7 ms). Threshold of stimulus intensity applied to T3 ganglia to achieve threshold was 3 times that of T1 threshold. ARIs in unstimulated states were unaffected by bilateral stellate-T2 ganglion removal. Following acute decentralization, T3 stimulation failed to change ARIs.

Conclusion

Preganglionic sympathetic efferents arising from the T1-T4 spinal cord that project to the heart transit through stellate ganglia via the paravertebral chain. T1-T2 surgical excision is thus sufficient to functionally interrupt central control of peripheral sympathetic efferent activity.

Keywords: stellate ganglion, sudden death, sympathetic efferent neurons, sympathectomy, ventricular arrhythmias, ventricular electrical indices

Introduction

Sudden cardiac death affects 180,000 – 250,000 patients in the United States per year 1. Patients with structural heart disease are at risk of ventricular arrhythmias that progress to sudden cardiac death (SCD) 1, 2. Although these conditions can usually be treated with medication 3, many are refractory to multiple medications 2, 4. Catheter ablation of select patients has proven to be an effective follow-up treatment option in many such cases 5. Despite these approaches, there remain subsets of patients who are refractory to these therapies and experience incessant ventricular arrhythmias 6, some with a high risk for SCD 4, 7, 8.

In those patients deemed unsuitable or unresponsive to such standard pharmacological or ablation therapies, modulation of the autonomic nervous system is emerging as an effective adjunct therapy 8–10. This approach is supported by the recognition of the importance of the cardiac nervous system in the progression of cardiac pathologies 2, 11–13. In an emergency setting, high thoracic spinal epidural anesthesia can be used to transiently stabilize cardiac electrical function 9. For sustained treatment, bioelectric therapies applied to the thoracic dorsal columns 10, 14, 15 or surgical approaches 4, 7, 8 applied to the paravertebral chain can modulate autonomic imbalances and reduce arrhythmias. For the surgical approach, bilateral stellate ganglion resection imparts anti-arrhythmic effects in patients with refractory ventricular tachycardia 7, 8. Such a surgical procedure removes all connections from spinal cord neurons to adrenergic and other neuronal somata in the thorax. Recently, this surgical approach has been modified to surgically remove the caudal 2/3 of the stellate ganglion along with their respective paravertebral chains down to the T4 paravertebral ganglia bilaterally 7, 8. While such surgical approaches have documented anti-arrhythmic effects 7, 8, removal of T3 –T4 ganglia frequently results in off-target adverse symptoms such as upper thoracic and limb hyperhidrosis/hyperalgesia 8, 16–18.

Within the literature there is a fundamental discrepancy between gross anatomy and tracer-based technologies to delineate structure/function organization of central (spinal cord) to peripheral interactions for the sympathetic nervous system. Gross anatomical studies routinely depict an intra-thoracic anatomy where multiple nerves course medially to the heart from the T1 level of the paravertebral chain down to either T5 or T6 paravertebral chain ganglia 19–23. Functional studies confirm that cardiac-related sympathetic efferent preganglionic neurons originate in the intermediolateral (IML) cell column of the spinal cord, project their axons via C7-T6 rami into the paravertebral chain 24, 25. From there, the cardiac related preganglionic fibers project to sympathetic efferent postganglionic neuronal somata contained in the superior cervical, middle cervical, mediastinal ganglia, and stellate ganglia 26. In contrast to most gross anatomical studies, functional studies, in a canine model, indicate that the primary interconnection between the stellate, middle cervical and mediastinal ganglia is via the dorsal and ventral ansae subclavian 27.

The objective of this study was to evolve a new surgical paradigm for bilateral stellectomy that was effective in interrupting central/peripheral interactions for efferent sympathetic projections to the heart, while at the same time maintaining as much of the paravertebral chain as possible. Achievement of this goal would maximize the therapeutic effects on the heart while minimizing damage to sensory and sympathetic motor control of upper limb, neck and thoracic wall. Data from this study indicate selective removal of the T1-T2 elements of the paravertebral chain are sufficient to achieve therapeutic goals in that no sympathetic efferent fibers project from lower chain (T3-T4) ganglia to the heart except through the stellate ganglia and then via the ansae subclavia to other intrathoracic autonomic ganglia. As a corollary, by leaving the cranial portions of both stellate ganglia (inferior cervical ganglia) intact, as is done clinically 7, 8, one can minimize any risk of Horner’s syndrome 28 and preserve major elements of intrathoracic ganglia for cardiac control 26. Moreover, by maintaining elements of the paravertebral chain below the stellate ganglion intact one minimizes the potential for upper limb and thoracic wall pain syndromes and hyperhidrosis

Methods

Institutional Review Board (IRB) approval was obtained for this protocol. The animal experimental protocol was performed in accordance with guidelines set by the University of California Institutional Animal Care and Use Committee and the National Institute of Health Guide of the Care and Use of Laboratory Animals.

Surgical preparation

Male Yorkshire pigs (n=8) weighing an average of 86±5 lbs were tranquilized and then anesthetised with telazol (8–10mg/kg, intramuscular) in the supine position. Following endotracheal tube placement, the animals were ventilated. General anaesthesia was introduced and maintained using isoflurane (1–1.5%, inhalation) and intermittent boluses of fentanyl (50–100ug/kg intravenous (iv)) as required. Following completion of surgery, anaesthesia was changed to α-chloralose (50mg/kg bolus followed by continuous infusion of 10mg/kg/hour iv). The right femoral artery was cannulated to monitor arterial blood pressure. Another catheter was inserted into the right femoral vein for fluid and drug administrations. Heart rate was monitored via limb leads. End tidal CO2 was maintained between 35–40mmHg. Arterial blood gas sampling was performed to assure maintenance of adequate oxygenation. In order to maintain blood gas homeostasis, hourly adjustments were made in tidal volume along with bolus administrations of appropriate doses of sodium bicarbonate.

A median sternotomy was performed to expose the heart and the stellate ganglia and paravertebral sympathetic chains caudal to the T4 ganglia. The cervical vagi were transected bilaterally. Thereafter, preparations were allowed to stabilize for one hour. At the end of each experiment, animals were euthanized by intravenous administration of a lethal dose of sodium pentobarbital (100 mg/kg/iv).

Hemodynamic indices

To measure left ventricular (LV) pressure, a 5-French pig tail associated with a 12-pole conductance catheter was inserted into the LV chamber via the left carotid artery. This device was connected to a MPVS Ultra Pressure Volume Loop System (Millar Instruments, Houston, TX). Catheter placement was confirmed using cardiac ultrasound and by examining the appropriate pressure and volume signals.

Stellate ganglion vs T3 paravertebral ganglion stimulations

The right and left stellate ganglia (LSG, RSG,) were stimulated individually via bipolar needle electrodes. Then the right and left T3 sympathetic chain ganglia in the paravertebral gutter were stimulated individually via bipolar needle electrodes. Bipolar electrodes were interfaced to Grass S88 Stimulators (Grass Co., Warwick, RI) via SIU6 constant current stimulus isolation units. Square wave stimulation pulses (4 Hz; 4 ms duration) were delivered individually to each site. Stimulation thresholds were defined as the stimulation current strength just sufficient to elicit a 10% increase of left ventricular end-systolic pressure (LVESP). For each stimulation site, the stimulus intensity employed thereafter was 1.5x threshold, applied for 30 second periods at 4Hz and 4 ms duration. A 10 minute resting period was allowed between each of these stimulations.

ARI recording and analysis

A custom 56-electrode sock was placed over both ventricles to measure unipolar epicardial electrograms derived from the ventricular epicardium via a Prucka CardioLab (GE Healthcare, Fairfield, CT) system (Figure 1 A & B). Activation recovery intervals (ARIs) were calculated using customized software (ScalDyn M; University of Utah, Salt Lake City, UT). Ventricular activation times (AT) were measured from the beginning of the first derivative of derived voltage (dV/dt) in the depolarization wave of the intrinsic deflection of voltage. Ventricular electrical recovery times were measured as the time of max dV/dt to time of the peak of the repolarization wave (T wave). ARIs were then calculated as AT subtracted from RT. This index has been shown to correlate with regional ventricular action potential durations (APDs) 29, 30. Global dispersion of repolarization (DOR) was calculated using the variance of all 56-electrode ARIs to demonstrate spatial dispersion of ventricular epicardial electrical repolarization.

Figure 1. Recording Array and Neural Anatomy.

Figure 1

Open in a new tab

An example of the custom 56-electrode sock placed over both ventricles to measure unipolar epicardial electrograms derived from the ventricular epicardium (B). Each electrode is color coded to correspond to a numbered specific region on the sock so that regional information can be obtained (A). Panel C schematically depicts the gross anatomical arrangement of the porcine right-sided upper thoracic paravertebral chain (T2-T4) and associated mediastinal neural structures including stellate and middle cervical (MCG) ganglia. X represents thoracic vagosympathetic trunk.

Protocols

Regional ventricular epicardial electrical function and indices of LV contractility (dP/dt) were evaluated at baseline and in response to stimulation of individual stellate ganglia (right stellate stimulation: RSS or left stellate stimulation: LSS) and with corresponding same side stimulation of the T3 paravertebral sympathetic ganglia. Thereafter, the caudal ½ portion of the stellate ganglion was removed along with the chain down to and including T2 ganglia (Fig 1C). Following a 20 min recovery period, the T3 chain ganglia were re-stimulated. Similar studies were then performed on contralateral stellate and intrathoracic chain sympathetic chain ganglia to T4. We alternated the side of the thorax in which the ganglia were first studied among animals.

Statistical analysis

Statistical analysis was performed using Sigma Stat with one-way repeated ANOVA for comparing hemodynamic and regional ventricular electrical indices before and after decentralization as well as comparing responses elicited by ganglionic stimulations in intact vs decentralized states. Paired Student’s t-test and Wilcoxon rank sum were performed for comparison of continuous variables. Data so compared were considered to be statistically significant if p<0.05. Data are presented as mean ± SE.

Results

Chronotropic and Dromotropic Responses

Intact. In intact states, right and left-sided stellate (T1) and T3 level paravertebral chain stimuli were titrated to produce equivalent changes in heart rate and LV ARI. Overall at 4 Hz, 4 ms duration, this was achieved at 1.2±0.1 mA (RT1) vs 8.7±1.8 mA (RT3) during right-sided stimuli and 3.2±0.3 mA (LT1) vs 11.4±0.3 mA (LT3) for left-sided stimuli. Compared to baseline, right-sided stellate (RT1) stimulation increased heart rate by 39±6 beats/min (p<0.05) while RT3 ganglionic stimulations increased heart rate by 22±3 beats/min (p<0.05) (Fig. 2A). Changes in whole heart ventricular ARI from baseline were induced from RT1 [86±11ms (26±9% change); p<0.05) vs RT3 [55±9ms (17±8% change); p<0.05] stimulation sites (Figs 2B). There was no significant difference statistically between T1 and T3 stimulations prior to stellectomy. Figure 3 demonstrates a polar map of whole heart ARI (ms) in one animal generated from the sock electrode comparing baseline intact conditions, with right stellate ganglion stimulation (RT1) (A), right T3 stimulation in the intact (RT3) (B), and post partial stellectomy (RT3 post SGX) (C).

Figure 2. Heart Rate and ARI Responses to Right T1 and T3 Stimulation Pre and Post Stellectomy.

Figure 2

Open in a new tab

Heart rate (A) and % change in ventricular ARI (B) compared to baseline (BL) in response to right-sided stellate (RT1) and T3 paravertebral (RT3) chain ganglion stimulation pre- (intact) and post- right-sided surgical excision of the caudal stellate ganglia and adjacent T2 chain ganglia (SGx). * p<0.05 compared to baseline; # p<0.05 compared to intact state.

Figure 3. Cardiac ARI Maps Pre and Post Stellate Removal.

Figure 3

Open in a new tab

An example of polar maps of ARI (ms) in one animal, generated from the sock electrode, are shown comparing baseline intact conditions, with right stellate ganglion stimulation (RT1) (A) and right T3 stimulation in the intact (RT3) state (B), vs. T3 stimulation post partial stellectomy (RT3 post SGx) (C). There is significant ARI shortening with RT1 and RT3 stimulation in the intact condition. When RT3 is stimulated post partial stellectomy there is no significant change in ARI from baseline.

Compared to baseline in the intact state, while heart rate was minimally affected by left-sided stellate (LT1) or LT3 stimuli (Fig 4A), changes in whole heart ventricular ARI were induced from both sites (Fig 4B) [LT1: 24±4ms (7±3% change), p<0.05; LT3: 18±4ms (5±1%): p<0.05]. The percentage change from baseline in whole heart ARI was significant comparing stimulation pre- (intact) and post- surgical excision of the caudal stellate ganglia and adjacent T2 ganglia (p<0.05) (Fig 4B). Whole heart dispersions in ARI, indicative of differential patterns of sympathetic innervation, failed to show a statistical significance across right side conditions T1 vs T3 stimulation intact and post partial stellectomy (Figure 5). However, paired comparison of left-sided evoked whole heart dispersions in ARI to T3 stimulation pre- to post partial stellectomy was significant.

Figure 4. Heart Rate and ARI Responses to Left T1 and T3 Stimulation Pre and Post Stellectomy.

Figure 4

Open in a new tab

Heart rate (A) and % change in ventricular ARI (B) compared to baseline (BL) in response to left sided stellate (LT1) and T3 paravertebral (LT3) chain ganglion stimulation pre- (intact) and post- left-sided surgical excision of the caudal stellate ganglia and adjacent T2 chain ganglia (SGx). * p<0.05 compared to baseline; # p<0.05 compared to intact state.

Figure 5. Dispersion of Repolarization in Response to T1 and T3 Stimulation Pre and Post Stellectomy.

Figure 5

Open in a new tab

Whole heart dispersion (ms2) for right (A) and left (B) T1 and T3 stimulation compared to baseline (BL) in the intact vs post partial stellectomy (SGx) state. * p<0.05 compared to baseline; # p<0.05 compared to intact LT3 stimulation.

Chronotropic and Dromotropic Responses: Post-stellectomy

Following surgical removal of the caudal portions of the stellate ganglia and T2 paravertebral ganglion, heart rate and ventricular ARIs did not change significantly from baseline. However, following these surgical procedures, chronotropic responses to subsequent RT3 stimulations were eliminated (Fig 2A). Minimal changes in heart rate to LT3 stimulation evoked in intact state did not change post left-side stellate-T2 resection (Fig 4A). For indices of cardiac epicardial electrophysiological function (ARI, Fig 2B, 4B; ARI dispersion Fig 5), these same surgical procedures completely mitigated all functional responses to subsequent T3 level stimulations.

Hemodynamics

In intact states, stimulation of right or left stellate ganglia increased left ventricular chamber dP/dt max (right: 93%; left: 68%; p<0.05 from baseline) (Fig 6). Similar effects were induced in this index of ventricular contractility when T3 ganglia were stimulated (right: 71%; left: 25%: p<0.05 from baseline). Following ipsilateral partial stellectomy, subsequent same-sided T3 ganglion stimulation failed to enhance LV dP/dt.

Figure 6. Ventricular dP/dt responses to Right and Left T1 and T3 Stimulation Pre and Post Stellectomy.

Figure 6

Open in a new tab

Change in right ventricular dP/dt maximum in response to right-sided (panel A) and left-sided (panel B) T1 and T3 stimulation compared to baseline (BL) in intact state and following surgical excision of the caudal stellate ganglia and adjacent T2 chain ganglia (SGx). * p<0.05 compared to baseline; # p<0.05 compared to intact state.

Discussion

The functional data derived herein demonstrate that cardiac-related preganglionic sympathetic axons arising from the lower cervical to upper thoracic (T1-T4) spinal cord project through the paravertebral chain to the stellate ganglia and from there through the ansae subclavia to all intrathoracic cardiac-related sympathetic ganglia. In other words, there are no nerves that arise from the paravertebral sympathetic chains that project medially directly to the heart.

In the 1930s stellectomy became a treatment strategy for pain and other therapies, involving as it did on total extirpation of left-sided stellate ganglia 20, 28. However, the results proved to be varied and the relatively extensive nature of this surgical approach frequently resulted in untoward side effects including abdominal hyperhidrosis, thoracic and upper limb pain 28. In the 1980’s, left-side stellectomy was proposed as adjunct therapy for treatment of ventricular arrhythmias 31. This anti-arrhythmia management strategy has evolved and bilateral caudal stellectomies combined with removal of thoracic sympathetic chain ganglia down to the T4 ganglia is becoming the standard of care 8, 32, 33. The results herein demonstrate that removal of the lower third of T1 and the T2 paravertebral ganglion is sufficient to decentralize the sympathetic paravertebral ganglia from the heart with potentially less side effects. Validation of this in human studies will be crucial to develop a simplified cardiac sympathectomy procedure given the influence of surgical excision of both stellate ganglia on reducing ventricular arrhythmias7–9.

Anatomical-functional data is relevant when contemplating surgery involving removal of intrathoracic paravertebral sympathetic ganglia in the suppression of ventricular arrhythmias. By sparing the cranial aspects of the stellate ganglia bilaterally one minimizes the occurrence of Horner’s syndrome 34 while preserving major cardiac-related neural networks localized to this same region 26. Preserving T3 and the more caudal elements of the paravertebral chain also reduced the potential for off-target side effects such as abdominal hyperhidrosis, thoracic and upper limb pain 8, 16–18.

Functional studies demonstrate that cardiac-related preganglionic soma are localized within the intermediolateral cell column and localized to the lower cervical (C7-C8) to upper thoracic (T1-T4) spinal levels 24, 25. These soma project axons to post ganglionic soma localized to the stellate, middle cervical, mediastinal and intrinsic cardiac ganglia 35, 36. These ganglia each contain a complex neural network involving afferent and local circuit neurons in addition to the post-ganglionic sympathetic soma 37–40. Together, these intrathoracic ganglia function as part of a hierarchy for cardiac control with these more peripheral elements primarily engaged in cardio-cardiac reflexes 41.

Functional data indicate that many neuronal somata in stellate ganglia are local circuit in nature – that is second order neurons that interact with one another, as well as with adrenergic motor neurons in the control of cardiac indices 42, 43. Further, most cardiac-related motor neurons, as defined by tracer studies, are localized to the cranial aspects of the stellate ganglia 26. Thus, removing the caudal aspects of the stellate ganglia, leaving the cranial aspects, preserves the majority of cardiac-related stellate neurons 26. All other intrathoracic cardiac related sympathetic ganglia remain, but with their preganglionic inputs interrupted by the caudal stellectomy combined with T2 excision. This allows the system to retain capabilities for robust intrathoracic control of cardiac indices even in the chronic decentralized state 42, 43. It is for these reasons that these surgical procedures should be considered as a surgical decentralization of peripheral sympathetic ganglia from central influences and not as a cardiac sympathetic denervation. Future studies should consider the functional capabilities of these intrathoracic reflex control loops in response to stress (e.g. orthostatic, exercise), especially in the context of adaptations that will evolve from loss of central drive. Validation of this in human studies will be crucial for a simplified cardiac sympathectomy procedure.

Limitations

The limitations of this study include the fact that responses were evaluated in an anesthetized animal model and in the short-term after surgical excision of relevant neural structures. As such, the data may not translate completely to predict the function of the human intrathoracic sympathetic nervous system. Studies were also undertaken in normal animals and as such potential cardiac disease induced changes in central-peripheral interactions for cardiac control were not evaluated. What is evident regardless of these limitations, is the positive effects on electrophysiological stability following such surgical procedures as evaluated herein, especially in the context of bilateral stellate decentralization for therapeutic management of ventricular arrhythmias 7, 8. What is also pertinent is that these therapeutic objectives can be achieved by a more limited paravertebral excision (to T2), thus reducing the potential for off target effects that accompany excision of paravertebral ganglia caudal to that point.

Clinical Perspective.

Ventricular electrical storm may be treated with standard pharmacological therapies and ablation. In certain cases, despite our efforts, we are unable to terminate the electrical storm. In such cases, autonomic modulation with stellate decentralization is a therapy that can be considered and currently involves removal of T1-T4 of the paravertebral sympathetic chain. Clinical follow up of patients has demonstrated significant reduction in ventricular arrhythmic events with bilateral stellate decentralization but as a side effect they can experience compensatory hyperhidrosis and hyperalgesia. Manipulations of any aspect of the neural hierarchy for cardiac control have the potential to alter reflex control of the heart. In this paper, we have demonstrated in a porcine model that the T3-T4 paravertebral chain has no direct efferent connections to the heart except that which projects rostral to the stellate ganglia and from there via the ansae subclavian to the heart. This is contrary to previous understanding of the cardiac innervation from the sympathetic paravertebral ganglia based on anatomic and neural tracer studies but not functional data. We suggest that a more limited paravertebral excision (only the lower third of T1 and T2) needs to be performed to adequately decentralize peripheral aspects of the cardiac-related sympathetic nervous system from the CNS. By removing less of the sympathetic chain we expect to reduce off target side effects, thus improving patient care. Validation of this in human studies will be crucial for a simplified cardiac sympathetic decentralization procedure.

Acknowledgments

Sources of funding: Work supported by Heart, Lung and Blood Institute grants HL71830 (JLA) and HL84261 (KS).

Abbreviations

ARI

Activation recovery index

SCD

Sudden Cardiac Death

IML

Intermediolateral

IRB

Institutional Review Board

IV

Intravenous

LV

Left Ventricle

LSG & RSG

Left Stellate Ganglion and Right Stellate Ganglion

LVESP

Left ventricular end systolic pressure

AT

Activation time

dV/dt

Derived voltage

APDs

Action potential duration

DOR

Dispersion of repolarization

LSS & RSS

Left stellate stimulation & Right stellate stimulation

T1 & T3

First and third paravertebral ganglion

R & L

Right and Left

Footnotes

Competing interests

No authors report a conflict of interest with respect to these studies.

Author contributions: KS, JAA and JLA contributed to the conception and design of experiments. UB, KY and TT performed experiments and analysed the data. UB, JAA, KS and JLA drafted, edited and revised the manuscript. All authors approved the final version of the manuscript.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, Mariani R, Gunson K, Jui J. Epidemiology of sudden cardiac death: clinical and research implications. Progress in cardiovascular diseases. 2008 Nov-Dec;51:213–228. doi: 10.1016/j.pcad.2008.06.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Fukada K, Kanazawa H, Aizawa Y, Ardell JL, Shivkumar K. Cardiac innervation and sudden cardiac death. Circulation research. 2015 doi: 10.1161/CIRCRESAHA.116.304679. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Exner DV, Reiffel JA, Epstein AE, et al. Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. Journal of the American College of Cardiology. 1999 Aug;34:325–333. doi: 10.1016/s0735-1097(99)00234-x. [DOI] [PubMed] [Google Scholar]
  • 4.Schwartz PJ. Cardiac sympathetic denervation to prevent life-threatening arrhythmias. Nature reviews Cardiology. 2014 Jun;11:346–353. doi: 10.1038/nrcardio.2014.19. [DOI] [PubMed] [Google Scholar]
  • 5.Tung R, Vaseghi M, Frankel DS, et al. Freedom from Recurrent Ventricular Tachycardia after Catheter Ablation is Associated with Improved Survival in Patients with Structural Heart Disease. Heart rhythm: the official journal of the Heart Rhythm Society. 2015;2015 doi: 10.1016/j.hrthm.2015.05.036. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Heart rhythm: the official journal of the Heart Rhythm Society. 2014 Oct;11:e166–196. doi: 10.1016/j.hrthm.2014.07.024. [DOI] [PubMed] [Google Scholar]
  • 7.Ajijola OA, Lellouche N, Bourke T, Tung R, Ahn S, Mahajan A, Shivkumar K. Bilateral cardiac sympathetic denervation for the management of electrical storm. Journal of the American College of Cardiology. 2012 Jan 3;59:91–92. doi: 10.1016/j.jacc.2011.09.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Vaseghi M, Gima J, Kanaan C, Ajijola OA, Marmureanu A, Mahajan A, Shivkumar K. Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: intermediate and long-term follow-up. Heart rhythm: the official journal of the Heart Rhythm Society. 2014 Mar;11:360–366. doi: 10.1016/j.hrthm.2013.11.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Bourke T, Vaseghi M, Michowitz Y, Sankhla V, Shah M, Swapna N, Boyle NG, Mahajan A, Narasimhan C, Lokhandwala Y, Shivkumar K. Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation. Circulation. 2010 Jun 1;121:2255–2262. doi: 10.1161/CIRCULATIONAHA.109.929703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Grimaldi R, de Luca A, Kornet L, Castagno D, Gaita F. Can spinal cord stimulation reduce ventricular arrhythmias? Heart rhythm: the official journal of the Heart Rhythm Society. 2012 Nov;9:1884–1887. doi: 10.1016/j.hrthm.2012.08.007. [DOI] [PubMed] [Google Scholar]
  • 11.Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circulation research. 2014 May 23;114:1815–1826. doi: 10.1161/CIRCRESAHA.114.302589. [DOI] [PubMed] [Google Scholar]
  • 12.Armour JA. Potential clinical relevance of the ‘little brain’ on the mammalian heart. Experimental physiology. 2008 Feb;93:165–176. doi: 10.1113/expphysiol.2007.041178. [DOI] [PubMed] [Google Scholar]
  • 13.Kember G, Armour JA, Zamir M. Neural control hierarchy of the heart has not evolved to deal with myocardial ischemia. Physiological genomics. 2013 Aug 1;45:638–644. doi: 10.1152/physiolgenomics.00027.2013. [DOI] [PubMed] [Google Scholar]
  • 14.Ardell JL, Cardinal R, Beaumont E, Vermeulen M, Smith FM, Andrew Armour J. Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation. Autonomic neuroscience: basic & clinical. 2014 Dec;186:38–44. doi: 10.1016/j.autneu.2014.09.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Lopshire JC, Zhou X, Dusa C, Ueyama T, Rosenberger J, Courtney N, Ujhelyi M, Mullen T, Das M, Zipes DP. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation. 2009 Jul 28;120:286–294. doi: 10.1161/CIRCULATIONAHA.108.812412. [DOI] [PubMed] [Google Scholar]
  • 16.Gossot D, Kabiri H, Caliandro R, Debrosse D, Girard P, Grunenwald D. Early complications of thoracic endoscopic sympathectomy: a prospective study of 940 procedures. The Annals of thoracic surgery. 2001 Apr;71:1116–1119. doi: 10.1016/s0003-4975(01)02422-5. [DOI] [PubMed] [Google Scholar]
  • 17.Yuncu G, Turk F, Ozturk G, Atinkaya C. Comparison of only T3 and T3-T4 sympathectomy for axillary hyperhidrosis regarding treatment effect and compensatory sweating. Interact Cardiovasc Thorac Surg. 2013 Aug;17:263–267. doi: 10.1093/icvts/ivt160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Panhofer P, Gleiss A, Eilenberg WH, Jakesz R, Bischof G, Neumayer C. Long-term outcomes after endothoracic sympathetic block at the T4 ganglion for upper limb hyperhidrosis. Br J Surg. 2013 Oct;100:1471–1477. doi: 10.1002/bjs.9275. [DOI] [PubMed] [Google Scholar]
  • 19.Ellison JP, Williams TH. Sympathetic nerve pathways to the human heart, and their variations. The American journal of anatomy. 1969 Feb;124:149–162. doi: 10.1002/aja.1001240203. [DOI] [PubMed] [Google Scholar]
  • 20.Kuntz A, Morehouse A. Thoracic sympathetic cardiac nerves in man. Arch Surg. 1930;20:607–613. [Google Scholar]
  • 21.Mizeres NJ. The cardiac plexus in man. The American journal of anatomy. 1963;112:141–152. [Google Scholar]
  • 22.Saccomanno G. The components of the upper thoracic sympathetic nerves. J Comparative Neurology. 1943;79:355–378. [Google Scholar]
  • 23.Mitchell GAG. Cardiovascular Innervation. London: E. & S. Livingstone LTD; 1956. [Google Scholar]
  • 24.Norris JE, Foreman RD, Wurster RK. Responses of the canine heart to stimulation of the first five ventral thoracic roots. The American journal of physiology. 1974 Jul;227:9–12. doi: 10.1152/ajplegacy.1974.227.1.9. [DOI] [PubMed] [Google Scholar]
  • 25.Norris JE, Lippincott D, Wurster RD. Responses of canine endocardium to stimulation of the upper thoracic roots. The American journal of physiology. 1977 Dec;233:H655–659. doi: 10.1152/ajpheart.1977.233.6.H655. [DOI] [PubMed] [Google Scholar]
  • 26.Hopkins DA, Armour JA. Localization of sympathetic postganglionic and parasympathetic preganglionic neurons which innervate different regions of the dog heart. The Journal of comparative neurology. 1984 Oct 20;229:186–198. doi: 10.1002/cne.902290205. [DOI] [PubMed] [Google Scholar]
  • 27.Armour JA, Hopkins DA. Anatomy of the Extrinsic Autnonomic Nerves and Ganglia Innervating the Mammalian Heart. In: Randall WC, editor. Nervous Control of Cardiovascular Function. New York: Oxford University Press; 1984. pp. 21–67. [Google Scholar]
  • 28.White JC, Garrey W, Atkins JA. Cardiac Innervation: Experimental and clinical studies. Arch Surg. 1933;26:765–786. [Google Scholar]
  • 29.Ajijola OA, Yagishita D, Patel KJ, Vaseghi M, Zhou W, Yamakawa K, So E, Lux RL, Mahajan A, Shivkumar K. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context. American journal of physiology Heart and circulatory physiology. 2013 Oct 1;305:H1031–1040. doi: 10.1152/ajpheart.00434.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Millar CK, Kralios FA, Lux RL. Correlation between refractory periods and activation-recovery intervals from electrograms: effects of rate and adrenergic interventions. Circulation. 1985 Dec;72:1372–1379. doi: 10.1161/01.cir.72.6.1372. [DOI] [PubMed] [Google Scholar]
  • 31.Schwartz PJ. The rationale and the role of left stellectomy for the prevention of malignant arrhythmias. Annals of the New York Academy of Sciences. 1984;427:199–221. doi: 10.1111/j.1749-6632.1984.tb20785.x. [DOI] [PubMed] [Google Scholar]
  • 32.Ajijola OA, Vaseghi M, Mahajan A, Shivkumar K. Bilateral cardiac sympathetic denervation: why, who and when? Expert review of cardiovascular therapy. 2012 Aug;10:947–949. doi: 10.1586/erc.12.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Ajijola OA, Vaseghi M, Zhou W, Yamakawa K, Benharash P, Hadaya J, Lux RL, Mahajan A, Shivkumar K. Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle. American journal of physiology Heart and circulatory physiology. 2013 Feb 15;304:H579–588. doi: 10.1152/ajpheart.00754.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Kuntz A. The Autonomic Nervous System. 2. London: 1934. Enlarged and Thoroughly Revised, Etc. printed in America. [Google Scholar]
  • 35.Hopkins DA, Armour JA. Ganglionic distribution of afferent neurons innervating the canine heart and cardiopulmonary nerves. Journal of the autonomic nervous system. 1989 Apr;26:213–222. doi: 10.1016/0165-1838(89)90170-7. [DOI] [PubMed] [Google Scholar]
  • 36.Randall WC, Armour JA, Geis WP, Lippincott DB. Regional cardiac distribution of the sympathetic nerves. Federation proceedings. 1972 Jul-Aug;31:1199–1208. [PubMed] [Google Scholar]
  • 37.Ardell JL, Cardinal R, Vermeulen M, Armour JA. Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia. American journal of physiology Regulatory, integrative and comparative physiology. 2009 Aug;297:R470–477. doi: 10.1152/ajpregu.90821.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Armour JA. Activity of in situ stellate ganglion neurons of dogs recorded extracellularly. Canadian journal of physiology and pharmacology. 1986 Feb;64:101–111. doi: 10.1139/y86-016. [DOI] [PubMed] [Google Scholar]
  • 39.Armour JA. Functional anatomy of intrathoracic neurons innervating the atria and ventricles. Heart rhythm: the official journal of the Heart Rhythm Society. 2010 Jul;7:994–996. doi: 10.1016/j.hrthm.2010.02.014. [DOI] [PubMed] [Google Scholar]
  • 40.Armour JA, Janes RD. Neuronal activity recorded extracellularly from in situ canine mediastinal ganglia. Canadian journal of physiology and pharmacology. 1988 Feb;66:119–127. doi: 10.1139/y88-022. [DOI] [PubMed] [Google Scholar]
  • 41.Armour JA. Cardiac neuronal hierarchy in health and disease. American journal of physiology Regulatory, integrative and comparative physiology. 2004 Aug;287:R262–271. doi: 10.1152/ajpregu.00183.2004. [DOI] [PubMed] [Google Scholar]
  • 42.Armour JA. Synaptic transmission in the chronically decentralized middle cervical and stellate ganglia of the dog. Canadian journal of physiology and pharmacology. 1983 Oct;61:1149–1155. doi: 10.1139/y83-171. [DOI] [PubMed] [Google Scholar]
  • 43.Armour JA. Neuronal activity recorded extracellularly in chronically decentralized in situ canine middle cervical ganglia. Canadian journal of physiology and pharmacology. 1986 Jul;64:1038–1046. doi: 10.1139/y86-177. [DOI] [PubMed] [Google Scholar]

RESOURCES