Download Cardiac sympathetic innervation via middle cervical and stellate

Am J Physiol Heart Circ Physiol 312: H392–H405, 2017.
First published December 23, 2016; doi:10.1152/ajpheart.00644.2016.
RESEARCH ARTICLE
Cardiac Excitation and Contraction
Cardiac sympathetic innervation via middle cervical and stellate ganglia
and antiarrhythmic mechanism of bilateral stellectomy
Tadanobu Irie,1,2* Kentaro Yamakawa,2* David Hamon,1,2 Keijiro Nakamura,1,2 Kalyanam Shivkumar,1,2
and Marmar Vaseghi1,2
1
UCLA Cardiac Arrhythmia Center, Los Angeles, California; and 2Neurocardiology Research Center of Excellence, Los
Angeles, California
Submitted 26 September 2016; accepted in final form 16 December 2016
NEW & NOTEWORTHY Sympathetic activation in myocardial
infarction leads to arrhythmias and worsens heart failure. Bilateral
cardiac sympathetic denervation reduces ventricular tachycardia/ventricular fibrillation inducibility and mitigates effects of sympathetic
activation on dispersion of repolarization and T-peak to T-end interval
in infarcted hearts. Hemodynamic stability is maintained, as innervation via the middle cervical ganglion is not interrupted.
Listen to this article’s corresponding podcast at https://ajpheart.
podbean.com/e/anti-arrhythmic-mechanism-of-bilateral-stellectomy/.
* T. Irie and K. Yamakawa contributed equally to this work.
Address for reprint requests and other correspondence: M. Vaseghi, UCLA
Cardiac Arrhythmia Ctr., 100 Medical Plaza, Ste. 660, Los Angeles, CA 90095
(e-mail: [email protected]).
H392
autonomic nervous system; cardiac sympathetic denervation; stellectomy; ventricular arrhythmias; sympathetic nervous system
(MI) increases the risk of sudden cardiac death due to ventricular tachyarrhythmias [ventricular
tachycardia (VT)/ventricular fibrillation (VF)] (13) by causing
pathological cardiac (16, 34, 41) and neural (15, 44, 53)
remodeling. Sympathetic activation via the right or left stellate
ganglion increases T-peak to T-end (Tp-Te) interval, a marker
of sudden cardiac death (8, 33), and increases dispersion of
repolarization (DOR), predisposing to VT/VF (27, 44, 45, 50).
Left cardiac sympathetic denervation (CSD) has been reported
to decrease the burden of VT/VF in patients with hereditary
channelopathies, including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, who have
structurally normal hearts (4, 17, 38). In a small series of
patients with structural heart disease, bilateral CSD has shown
promise in reducing the burden of internal cardioverter defibrillator (ICD) shocks. This study also suggested that bilateral
CSD may lead to a greater ICD shock-free survival compared
with left CSD in patients with cardiomyopathy (43). However,
the electrophysiological mechanisms behind the reduction in
life-threatening arrhythmias with CSD are not clear. In addition, it is unknown how much of cardiac sympathetic innervation, which may be required for beat-to-beat function, is
preserved after bilateral CSD. The middle cervical ganglia
(MCGs), located anatomically superior to the stellate ganglia,
have been reported to contain cardiac sympathetic neurons (7,
21) and could provide sympathetic innervation after CSD.
However, their electrophysiological effects have not been characterized. The purpose of this study was to delineate 1) sympathetic innervation of the heart via the MCG compared with
the stellate ganglia, 2) electrophysiological and antiarrhythmic
effects of CSD, including VT inducibility, and 3) alterations in
functional cardiac sympathetic innervation after CSD and its
antiarrhythmic mechanisms in a porcine model.
MYOCARDIAL INFARCTION
METHODS
Study procedures were approved by the UCLA Institutional Animal Research Committee and were performed in compliance with the
National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Creation of myocardial infarcts. Eighteen Yorkshire pigs were
sedated (6 –10 mg/kg Telazol and 2–5 ␮g/kg fentanyl), intubated, and
placed under general anesthesia with inhaled isoflurane (0.5–1.5%).
After femoral arterial access was obtained with an 8-F sheath, an
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Irie T, Yamakawa K, Hamon D, Nakamura K, Shivkumar K,
Vaseghi M. Cardiac sympathetic innervation via middle cervical and
stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy. Am J Physiol Heart Circ Physiol 312: H392–H405, 2017. First
published December 23, 2016; doi:10.1152/ajpheart.00644.2016.—
Cardiac sympathetic denervation (CSD) is reported to reduce the
burden of ventricular tachyarrhythmias [ventricular tachycardia (VT)/
ventricular fibrillation (VF)] in cardiomyopathy patients, but the
mechanisms behind this benefit are unknown. In addition, the relative
contribution to cardiac innervation of the middle cervical ganglion
(MCG), which may contain cardiac neurons and is not removed
during this procedure, is unclear. The purpose of this study was to
compare sympathetic innervation of the heart via the MCG vs. stellate
ganglia, assess effects of bilateral CSD on cardiac function and
VT/VF, and determine changes in cardiac sympathetic innervation
after CSD to elucidate mechanisms of benefit in 6 normal and 18
infarcted pigs. Electrophysiological and hemodynamic parameters
were evaluated at baseline, during bilateral stellate stimulation,
and during bilateral MCG stimulation in 6 normal and 12 infarcted
animals. Bilateral CSD (removal of bilateral stellates and T2
ganglia) was then performed and MCG stimulation repeated. In
addition, in 18 infarcted animals VT/VF inducibility was assessed
before and after CSD. In infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response than stellate
ganglion stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in infarcted hearts and prolonged global activation
recovery interval. CSD mitigated effects of MCG stimulation on
dispersion of repolarization and T-peak to T-end interval in infarcted hearts, without causing hemodynamic compromise. These
data demonstrate that the MCG provides significant cardiac sympathetic innervation before CSD and adequate sympathetic innervation after CSD, maintaining hemodynamic stability. Bilateral
CSD reduces VT/VF inducibility by improving electrical stability
in infarcted hearts in the setting of sympathetic activation.
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ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
A
B
Subclavian Artery
MCG
Sympathetic Chain
D
on the epicardium was assessed in infarcted animals grossly (Fig. 1),
as well as by bipolar voltage measurements with a 2-2-2 duodecapolar
catheter [2-2-2 electrode spacing (mm), St. Jude Medical, St. Paul,
MN]. Regions with a voltage ⬍ 0.5 mV were defined as scar, those
with voltage of 0.5-1.5 mV were defined as border zone, and electrodes overlying regions with voltage ⬎ 1.5 mV were defined as
viable/normal (14, 23). The location and extent of infarct were marked
on the heart. The MCG were identified often above and behind the
subclavian artery, at the inlet of the thorax (Fig. 1) After completion
of the surgical portion of the procedure isoflurane was discontinued,
and an intravenous infusion of ␣-chloralose (10 –30 mg·kg⫺1·h⫺1)
was begun (5, 10, 11). During anesthesia with both ␣-chloralose and
isoflurane, heart rate (HR) as well as jaw tone and eyeblink reflexes
were monitored every 10 –15 min to ensure adequate sedation.
Stellate and middle cervical ganglion stimulation. Bipolar needle
electrodes (Fig. 1) were used for bilateral stellate ganglion stimulation
and bilateral MCG stimulation with a Grass Stimulator (model S88,
Grass Technologies, Warwick, RI) in both infarcted (n ⫽ 12) and
normal (n ⫽ 6) animals. Threshold was defined as the current needed
to increase HR or systolic blood pressure by 10% (at 4 Hz, 4 ms).
Stimulation was performed at 1.5 times threshold for 30 s. In
normal animals, the stimulation current used was 2.4 ⫾ 0.5 mA for
the right stellate ganglion and 2.3 ⫾ 0.4 mA for the right MCG; the
stimulation current was 5.6 ⫾ 0.8 mA for the left stellate ganglion and
6.0 ⫾ 0.7 mA for the left MCG. For infarcted animals, the stimulation
current used was 6.7 ⫾ 1.0 mA for the right stellate ganglion and
5.9 ⫾ 1.2 mA for the right MCG; the stimulation current was
Ansa Subclavia
C
Needle Electrode
Cardiopulmonary
Nerves
MCG
F
E
RV Ant
RVOT
LAD
RV Lat
RV
LV Ant
LAD
LV
LV Lat
RV Post
Apex
LV Post
Fig. 1. Isolation of the middle cervical ganglia (MCG) and Tp-Te interval and ARI recordings. A: anatomy of MCG and surrounding tissue is shown. The MCG
sits just at the thoracic inlet and provides cardiopulmonary nerves that innervate the heart. B: customized bipolar needle electrodes were placed in the isolated
MCG. C: method for the measurement of Tp-Te interval from surface ECG. The peak of the T wave was determined as the highest voltage of the T wave (T-p).
T-end (T-e) was determined by the tangent of the T wave. D: the region of scar in infarcted hearts predominantly involved the LV apex, anterior, and anterolateral
walls. E: 56-electrode sock is placed over the ventricles to obtain unipolar electrograms that are used for ARI analysis. F: template for the polar maps used to
display regional ARIs from the sock electrodes. Ant, anterior; Lat, lateral; Post, posterior; RVOT, right ventricular outflow tract.
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Amplatz guide catheter (Boston Scientific, Marlborough, MA) was
advanced over a J-tipped guide wire under fluoroscopic guidance and
used to cannulate the left main coronary artery from the left femoral
artery. A coronary angiogram was performed to delineate the branches
of the left anterior descending coronary artery (LAD). A 3-mm
luminal angioplasty balloon (Armada 35 PTA, Abbott Vascular,
Temecula, CA) was advanced past the first diagonal branch of the
LAD over a 0.014-in. coronary guide wire (Balance Middle Weight
wire, Abbott Vascular) and inflated. Polystyrene microspheres (5.0 –
7.5 ml, Polysciences, Warrington, PA) were injected through the
lumen of the percutaneous balloon catheter (26). Repeat coronary
angiography after microsphere injection showed confirmed poor
blood flow in the LAD after the first diagonal branch. Continuous
electrocardiogram (ECG) monitoring was performed. ECG changes
including ST segment elevation and or T-wave inversions were also
used to confirm MI acutely. If sustained VT/VF was observed,
resuscitation with chest compressions and external direct-current
cardioversion was performed. Animals were then extubated and monitored until they could ambulate without assistance.
Surgical preparation. Four to six weeks after MI, 18 infarcted
(48 ⫾ 2 kg) and 6 normal (43 ⫾ 1 kg) animals were sedated (6 –10
mg/kg Telazol and 2–5 ␮g/kg fentanyl) and placed under general
anesthesia with isoflurane (0.8 –1.5%). Normal animals had not undergone a percutaneous interventional procedure before terminal experiments. Median sternotomy was performed, and isolation of bilateral stellate ganglia and T2 thoracic ganglia (all animals) and bilateral
MCG (12 of 18 animals) was performed. Presence and extent of scar
H394
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
A Timeline of Experimental Protocol in Normal Animals
B
350
300
P < 0.05
350
300
LAD
12
LV
10
Apex
BL
8
6
LAD
RV
2
200
200
BL
BSGS
BL BMCGS
LAD
376
364
352
340
327
315
303
291
279
266
254
242
RV
4
250
250
P = 0.4
14
Change in ARI (%)
400
Global ARI (ms)
Global ARI (ms)
P < 0.05
0
LV
BSGS BMCGS
Apex
RV
LV
Apex
BL
LAD
RV
LV
ARI (ms)
BSGS
Apex
BMCGS
Fig. 2. Experimental protocol in normal hearts and effect of bilateral stellate ganglion stimulation (BSGS) compared with bilateral MCG stimulation (BMCGS).
A: timeline of the experimental protocol in 6 normal animals. HEX, hexamethonium. *BMCGS or BSGS was performed in a random order. B: in all normal
animals, BMCGS had an effect on ARI similar to that of BSGS. C: polar maps from a normal animal show the effects of MCG and stellate ganglion stimulation
on ARI. Blue dashed lines indicate course of left anterior descending coronary artery (LAD). BL, baseline.
9.8 ⫾ 1.0 mA for left stellate ganglion stimulation and 10.0 ⫾ 1.0 mA
for left MCG. In normal animals, a second stellate and MCG stimulation was performed before CSD for 60 s and electrophysiological
effects were compared at 5, 10, 15, 20, 30, 45, and 60 s. A 30-min
period was allowed for return of hemodynamic parameters to baseline
in between stimulations. The timeline for the experimental protocol in
normal animals is shown in Fig. 2.
Hemodynamic and electrocardiogram recordings. Hemodynamic
parameters were continuously recorded with a 12-pole conductance
pressure catheter in the left ventricle (LV), connected to a MPVS
Ultra Pressure Volume Loop System (Millar Instruments, Houston,
TX). ECG was continuously obtained with the GE Cardiolab System
(GE Healthcare). Tp-Te interval was assessed in the inferior leads
with the clearest T wave off-line manually from the electrocardiograms obtained from the Cardiolab System at 400 mm/s paper
speed. Tp-Te interval was measured from the peak of T wave to the
end of T wave. The peak of the T wave was visually determined,
and the end of the T wave was defined as the intersection of the
tangent to the slope of the T wave and the isoelectric line, when not
followed by a U wave (Fig. 1). If a U wave followed the T wave,
the offset of the T wave was measured as the nadir between the T
and U waves. This method is similar to what has been described in
the literature (29, 50).
Bilateral cardiac sympathetic denervation. Bilateral CSD was
performed in 18 infarcted and 6 normal animals after isolation of
bilateral stellate and T2 thoracic ganglia. T3 and T4 thoracic ganglia
were not removed, as it has been shown previously that cardiac fibers
from these ganglia traverse through the stellate and T2 ganglia before
reaching the heart (12). The lungs on each side were retracted,
the sympathetic chain was again identified, and its connections to the
spinal cord and cardiopulmonary nerves were transected. Both stellate
ganglia and T2 thoracic ganglia were removed. A 30-min stabilization
Table 1. Hemodynamic parameters in normal animals
BL (PreBSGS)
BSGS
BL (PreMCGS)
BMCGS (PreCSD)
HR, bpm
84 ⫾ 17
98 ⫾ 13*
89 ⫾ 14
1,178 ⫾ 166
2,391 ⫾ 724*
1,086 ⫾ 116
dP/dtmax, mmHg/s
dP/dtmin, mmHg/s ⫺1,126 ⫾ 317 ⫺1,149 ⫾ 462 ⫺1,172 ⫾ 337
LVESP, mmHg
103 ⫾ 20
147 ⫾ 23*
99.5 ⫾ 21
103 ⫾ 10*
2,364 ⫾ 531*
⫺1,174 ⫾ 302
134 ⫾ 24*§
PreCSD
PostCSD
86 ⫾ 12
89 ⫾ 8
1,032 ⫾ 157
1,087 ⫾ 296
⫺1,121 ⫾ 353 ⫺1,094 ⫾ 286
97.5 ⫾ 22
94 ⫾ 16
BL (PreMCGS
PostCSD)
BMCGS (PostCSD)
90 ⫾ 12
1,007 ⫾ 228
⫺984 ⫾ 266
87 ⫾ 13
104 ⫾ 10*
2,232 ⫾ 467*
⫺1,149 ⫾ 382
125 ⫾ 20*†
Values represent mean ⫾ SD % change in parameters from prestimulation value (n ⫽ 6). PreCSD represents hemodynamic values immediately before removal
of the stellate ganglia. PostCSD values represent hemodynamic parameters after a 30-min period of stabilization after removal of stellate ganglia. HR, heart rate;
bpm, beats per minute; dP/dtmax, dP/dtmin, maximum and minimum dP/dt; LVESP, left ventricular end-systolic pressure; BL, baseline; BSGS, bilateral stellate
ganglion stimulation; BMCGS, bilateral middle cervical ganglion stimulation. *P value ⬍ 0.05 for % change from baseline (prestimulation). †P ⫽ 0.08 for %
increase in LVESP with BMCGS PreCSD vs. PostCSD. §P ⫽ 0.02 for comparison of % change in LVESP for BSGS vs. BMCGS.
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400
C
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
Table 2. Norepinephrine levels in normal and infarcted
animals
Normal pigs (CS)
Normal pigs (IVC)
Infarct pigs (CS)
Infarct pigs (IVC)
Baseline
BSGS
Baseline
0.38 ⫾ 0.09
0.58 ⫾ 0.22
1.35 ⫾ 0.41
1.97 ⫾ 0.54
8.70 ⫾ 2.28*
1.52 ⫾ 0.29*
7.47 ⫾ 1.48*
2.53 ⫾ 0.28
BMCGS
0.54 ⫾ 0.16 13.73 ⫾ 4.47*
0.55 ⫾ 0.07 1.61 ⫾ 0.29*
1.79 ⫾ 0.51 7.83 ⫾ 2.16*
1.89 ⫾ 0.46 3.78 ⫾ 0.95*
Values (in ng/ml) are means ⫾ SE. CS, coronary sinus; IVC, inferior vena
cava; BSGS, bilateral stellate ganglion stimulation; BMCGS, bilateral middle
cervical ganglion stimulation. *P ⬍ 0.05 compared with baseline.
BSGS
Percent Change in ARI (%)
A
BMCGS Pre-CSD
0
-5
-10
-15
-20
-25
5sec
B
10sec
15sec
20sec
30sec
45sec
30
Change in ARI (%)
connected to a MicroPace stimulator (MicroPace EP, Santa Ana, CA).
Current was set at two times the ventricular capture threshold in each
animal with a pulse duration of 1 ms. If VT/VF was not induced from
the RV endocardium at baseline before CSD, a second site on the LV
epicardium close to the scar was used before CSD. The same or a very
similar site was used for induction of VT/VF after CSD as had been
used to induce VT/VF before CSD. The induction protocol was as
follows: an extrastimulus was placed after 8 beats of drive cycle
length (at 500 ms) at an interval of 400 ms (S2). The premature
extrastimulus interval (S2) was reduced by 10 ms until either an
interval of 200 ms or an ERP was reached or VT/VF was induced. If
VT/VF was not induced, then S2 was fixed at 20 ms above the ERP
or at 220 ms (if ERP was ⬍200 ms) and a second premature
extrastimulus (S3) was added at an interval of 400 ms. The S3 interval
was then reduced by 10 ms until an S2–S3 interval of 200 ms or ERP
was reached or VT/VF was induced. Finally, if no VT/VF was
induced, then the S3 interval was set at 220 ms (if ERP was ⬍200 ms)
or 20 ms above ERP and an S4 interval (triple extrastimulus) was
added at an S3–S4 interval of 400 ms. This S4 interval was then
reduced by 10 ms until a coupling interval of 200 ms or effective
period was reached or VT/VF was induced. Inducibility was defined
60sec
BSGS
BMCGS Pre-CSD
25
20
15
10
5
0
Apex
Ant
Lat
Post
Post
Lat
LV
C
Global ARI (ms)
260
Ant
RVOT
RV
P < 0.05
Fig. 3. A: the time course of ARI shortening with bilateral
stellate ganglion stimulation (BSGS) was similar to that with
bilateral MCG stimulation (BMCGS) (n ⫽ 6). B: there were
no significant regional differences between BSGS and
BMCGS in normal hearts (P values ⬎ 0.05 for all regions,
n ⫽ 6). C: apical ventricular pacing before CSD demonstrated
shorter global ARIs than right atrial (RA) pacing in normal
animals (n ⫽ 6) at the same cycle lengths. However, after
CSD there was no significant difference in ARI between
ventricular and atrial pacing, suggesting that apical pacing
may cause reflex sympathetic activation that is prevented by
CSD. Ant, anterior; Lat, lateral; Post, posterior wall; RV, right
ventricle; LV, left ventricle.
RA Pacing
Apical Pacing
P = 0.6
250
P = 0.5
240
P < 0.05
230
220
210
200
BL Pre-CSD
BMCGS Pre-CSD
Pre-CSD
BL Post-CSD
BMCGS Post-CSD
Post-CSD
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period after CSD was allowed before repeat stimulation or inducibility
testing. VT/VF inducibility was tested before and after CSD.
Inducibility testing for ventricular tachyarrhythmias. In 18 infarcted hearts, programmed ventricular stimulation up to triple extrastimuli to a minimum coupling interval of 200 ms or an effective
refractory period (ERP) was performed before and after CSD first
from the right ventricular (RV) endocardium at the mid- to apical
septum with an endocardial quadripolar electrophysiology catheter
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H396
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
as hemodynamically tolerated VT that lasted ⬎30 s or that degenerated into VF requiring direct cardioversion.
Measurement of norepinephrine levels. Norepinephrine (NE) levels
in the inferior vena cava (IVC) and coronary sinus (CS) were measured to confirm adequate ganglion stimulation. Venous blood was
obtained from a luminal catheter inserted in the IVC, superior to the
adrenal veins and close to the right atrium. CS blood was obtained by
cannulation of the CS with a luminal catheter (St. Jude Medical, St.
Paul, MN) from the right external jugular vein. Blood samples at
baseline and in the last 5 s of stellate ganglion and MCG stimulation
before CSD were immediately centrifuged (3,000 rpm, 15 min) to
separate the plasma portion. Quantification of NE was performed with
A
B
PreCSD
PostCSD
ARI (ms)
C
300
BMCGS Post-CSD
*
*
*
*
*
250
200
Apex
Ant
Lat
Post
300
250
BL
20
P = 0.6
15
10
5
0
BMCGS
PreCSD
Post
Lat
LV
Ant RVOT
BMCGS Pre-CSD
BMCGS Post-CSD
20
10
0
Apex
Ant
RV
Lat
Post
Post
Lat
Ant
RVOT
RV
LV
D
PostCSD
30
E
800
800
P<0.05
700
600
600
DOR (ms2)
700
500
400
300
Normal Hearts
Post-CSD - Normal Hearts
80
P<0.05
Tp-Te Interval (ms)
Pre-CSD - Normal Hearts
500
400
P=0.1
P=0.1
60
40
20
300
200
200
BL
BMCGS
BMCGS
80
P=0.9
60
40
20
0
0
BL
Percent Change in Tp-Te (%)
ARI (ms)
*
350
25
Post-CSD
BL
*
P < 0.03
200
400
350
Percent Change in ARI (%)
Global ARI (ms)
250
Pre-CSD
Percent change in ARI (%)
Global ARI (ms)
300
400
BMCGS
BL
BMCGS
Pre-CSD
BL
BMCGS
Post-CSD
PreCSD
PostCSD
Fig. 4. Effects of CSD in normal animals. A: there was no difference in global ARI in normal heart before compared with after CSD. B: bilateral MCG stimulation
after CSD had similar effects on global ARI compared with before CSD, with significant ARI shortening observed. C: there were no differences in the regional
effects of MCG stimulation after CSD compared with before CSD. *P ⬍ 0.05; †P ⬍ 0.1. D: before CSD bilateral MCG stimulation increased dispersion of
repolarization in normal hearts, and this effect was not modified by CSD. E: bilateral MCG stimulation in normal hearts also increased Tp-Te interval, with no
differences observed in this parameter before compared with after CSD in normal hearts.
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350
200
Post-CSD
355
349
342
336
329
323
316
310
303
297
291
284
P = 0.2
400
DOR (ms2)
an ultrasensitive enzyme-linked immunoassay (ELISA) (BA E-5200,
sensitivity 1.3 pg/ml, Labor Diagnostika Nord, Nordhorn, Germany)
and an ELISA microplate reader (Fisher Scientific, Waltham, MA).
Activation recovery interval recordings. In 12 infarcted and 6
normal animals, detailed electrophysiological mapping was performed. A 56-electrode sock (Fig. 1) was placed over the ventricles to
assess activation recovery interval (ARI), a surrogate of local action
potential duration. Unipolar electrograms were recorded (0.05–500
Hz) with the GE Cardiolab System. ARIs were calculated with
customized software (ScalDyn, University of Utah, Salt Lake City,
UT) as previously described (44, 46). Briefly, activation time (AT)
was defined as the interval from electrogram onset to most negative
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
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Preganglionic vs. postganglionic neural fibers within MCG. To
evaluate presence of pre- vs. postganglionic fibers within the MCG in
normal animals after CSD, bilateral MCG stimulation was repeated
after infusion of hexamethonium, a nicotinic receptor blocker. Right
vagal nerve stimulation (VNS) was also performed before and after
hexamethonium infusion to ensure nicotinic receptor blockade, as
vagal efferent parasympathetic fibers are known to be preganglionic.
The right cervical vagal trunk was isolated via a lateral neck cutdown,
and bipolar needle electrodes (Cyberonics, Houston, TX) attached to
a Grass stimulator were used for right VNS (10 Hz, 1 ms). Threshold
was defined as the current at which HR decreased by 10%, and
stimulation was performed at 1.2 times threshold for 20 s, before and
after hexamethonium. Hexamethonium was infused for 30 min
(0.025– 0.2 mg·kg⫺1·min⫺1, dose titrated by response to right VNS in
each animal).
Statistical analysis. Unless specified otherwise, data are presented
as means ⫾ SE. Global ARI was calculated as the mean ARI across
all 56 electrodes. Global DOR was calculated as the variance in ARIs
across all 56 electrodes. For comparison of paired variables, Wilcoxon
signed-rank test or paired t-test was used was used. Sample size of
infarcted animals was driven by the assumption of a 40% reduction in
VT/VF inducibility after CSD with 80% power to detect this reduction
at an ␣ of 0.05. McNemar’s test was used to compare VT inducibility
before and after CSD. Sample size of normal animals was driven by
80% power to detect a 10% difference in the effects of MCG vs.
stellate ganglion stimulation on global ARI in the same animal at an
␣ of 0.05. The Mann-Whitney test was used for comparison of
A
MCG Stim
B
Right VNS
P < 0.05
400
400
P < 0.05
Global ARI (ms)
Global ARI (ms)
P = 0.6
350
300
350
300
250
250
C
Percent Change in ARI (%)
P = 0.3
12
10
8
P < 0.05
Fig. 5. Effects of hexamethonium on MCG stimulation. A: the increase in global ARI during
right vagal nerve stimulation (VNS) was no
longer observed after infusion of hexamethonium (Hex) in normal animals (n ⫽ 6). B: global
ARI during bilateral MCG stimulation significantly decreased even after administration of
hexamethonium in all normal hearts (n ⫽ 6). C:
% change in global ARI during right VNS and
bilateral MCGS stimulation showed that hexamethonium significantly blocked nicotinic receptors but did not affect the response to bilateral MCG stimulation.
P < 0.05
6
4
2
0
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dV/dt of the activation wave, and repolarization time (RT) was defined
as the interval from electrogram onset to the most positive dV/dt of the
repolarization wave. ARI was defined as the difference between RT
and AT. Map3D software (University of Utah, Salt Lake City, UT,
http://www.sci.utah.edu/cibc-software/map3d.html) was used to map
the epicardial pattern of activation and ARI with a sock-electrode
polar map template (Fig. 1F). Global DOR was calculated as the
variance of ARIs recorded across all epicardial electrodes.
In this article, “anterior” refers to the ventral and “posterior” to the
dorsal aspect of the heart. In normal animals, mean ARIs in the
following regions were analyzed on the basis of electrode location:
LV apex, LV anterior, LV lateral, and LV posterior wall and RV
anterior, RV lateral, RV posterior wall, and RV outflow tract. A
median of three electrodes (range 2– 4) per region were used for
regional ARI and AT analysis.
Atrial and ventricular pacing. To evaluate the effect of CSD on
ARI during ventricular pacing compared with atrial pacing, ventricular pacing was performed at baseline and during MCG stimulation
before and after CSD (pacing cycle length ⫽ 400 ms or 500 ms,
depending on HR during stimulation) in six normal and five infarcted
animals. To compare differences to ventricular pacing, right atrial
pacing at the same cycle length was performed in normal animals at
baseline and during bilateral MCG stimulation, before and after CSD.
In addition, Map3D software (University of Utah) was used to map
the epicardial pattern of activation and ARI during scar pacing in five
infarcted hearts. The template, with sock electrode locations, used for
creation of these polar maps is shown in Fig. 1.
H398
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
continuous variables in different groups. Percent change in regional
ARIs for stellate ganglion vs. MCG stimulation were analyzed with
repeated-measures ANOVA after controlling for false discovery rate
at 5%. SPSS (version 22, IBM, Armonk, NY) was used for statistical
analysis. P ⬍ 0.05 was considered statistically significant.
RESULTS
A
Timeline of Creation of Myocardial Infarct and Mapping Experiments in Infarcted Animals
C
B
350
300
400
Apex
20
BL
15
300
LAD
10
250
200
200
BSGS
424
402
379
357
334
312
289
267
244
222
200
177
25
350
250
BL
LAD
RV
LV
Change in ARI (%)
Global ARI (ms)
Global ARI (ms)
P < 0.01
400
P = 0.02
P < 0.01
RV
5
LV
0
BL
BMCGS
BSGS
BMCGS
Apex
ARI (ms)
BSGS
LAD
RV
LV
Apex
BL
LAD
RV
LV
Apex
BMCGS
Fig. 6. Experimental protocol in infarcted hearts and effect of bilateral stellate ganglion stimulation (BSGS) compared with bilateral MCG stimulation (BMCGS).
A: timeline of the experimental protocol in 12 infarcted animals. *BMCGS or BSGS was performed in a random order. B: in all infarcted animals BSGS
significantly decreased ARI, as did BMCGS. BMCGS, however, caused greater ARI shortening than BSGS. C: polar maps from an infarcted animal show the
effects of MCG and stellate ganglion stimulation on ARI. Black dashed circle indicates region of the infarct/scar on polar maps. Blue dashed lines indicate course
of left anterior descending coronary artery (LAD). BL, baseline.
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Thoracic sympathetic innervation in normal hearts. The
timeline for the experimental protocol in normal animals is
shown in Fig. 2. In normal hearts bilateral stellate ganglion and
bilateral MCG stimulation significantly increased HR, maximum dP/dt (dP/dtmax) and LV end-systolic pressure (LVESP)
(Table 1). Comparison of bilateral stellate ganglion to bilateral
MCG stimulation demonstrated no differences in the HR or
dP/dtmax increase. However, bilateral stellate ganglion stimulation had a greater effect on LVESP than bilateral MCG
stimulation. CS NE levels increased in a similar fashion during
bilateral stellate and bilateral MCG stimulation compared with
prestimulation values (Table 2).
Both bilateral stellate ganglion and MCG stimulation decreased epicardial ARI (Fig. 2). There was no significant
difference in the time course of ARI shortening during the 60
s of stimulation between the stellate ganglia and MCG (Fig.
3), and no differences in regional ARIs were detected
between bilateral stellate ganglion and bilateral MCG stimulation (Fig. 3).
Compared with right atrial pacing, LV apical pacing at
baseline and during MCG stimulation at the same cycle length
led to significantly shorter epicardial ARIs (P ⬍ 0.05), sug-
gesting that ventricular pacing alone led to cardiac sympathetic
activation (Fig. 3).
CSD and residual sympathetic innervation in normal hearts.
CSD did not cause hemodynamic deterioration in normal
hearts (Table 1). No difference in global ARI was observed
before compared with after CSD (Fig. 4).
MCG continued to exert significant sympathetic effects after
CSD. Global ARI continued to decrease during MCG stimulation after CSD (Fig. 4). Effects of bilateral MCG stimulation
after CSD on HR and dP/dtmax were unchanged compared with
before CSD (Table 1). Of note, comparison of atrial to ventricular pacing at the same cycle length showed that the
differences in ARI shortening between right atrial pacing and
LV pacing were no longer significant after CSD, with or
without MCG stimulation (Fig. 3). DOR and Tp-Te interval,
which increased during MCG stimulation, were unaffected by
CSD in normal hearts (Fig. 4). Furthermore, CSD had no effect
on activation time [pre-CSD: baseline 26.1 ⫾ 1.5 ms vs. MCG
stimulation 30.4 ⫾ 4.1 ms (P ⫽ 0.3); post-CSD: baseline
26.1 ⫾ 1.1 ms vs. MCG stimulation 28.2 ⫾ 1.5 ms (P ⫽ 0.2)].
To evaluate presence of preganglionic fibers within the
MCG, response to hexamethonium was evaluated. Right VNS
was also performed to ensure adequate nicotinic receptor
blockade. Global ARI significantly increased during right VNS
before hexamethonium infusion (Fig. 5). After hexamethonium
infusion, there was no change in global ARI during right VNS.
However, the effects of MCG stimulation after hexamethonium were unchanged, suggesting the presence of predominantly postganglionic sympathetic fibers in the MCG (Fig. 5).
H399
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
Table 3. Hemodynamic parameters in infarcted animals
BL (PreBSGS)
BSGS
BL (PreBMCGS)
BMCGS (PreCSD)
PreCSD
BL (PreMCGS
PostCSD)
PostCSD
HR, bpm
85 ⫾ 10.7
94 ⫾ 21*
84 ⫾ 11.8
112 ⫾ 22*§
83 ⫾ 13
84 ⫾ 13
84 ⫾ 13
1,246 ⫾ 390
2,127 ⫾ 315*
1,123 ⫾ 332
2271 ⫾ 9678*†
984 ⫾ 349
880 ⫾ 337
878 ⫾ 338
dP/dtmax, mmHg/s
⫺1,090 ⫾ 571 ⫺1,025 ⫾ 634 ⫺1,027 ⫾ 630
dP/dtmin, mmHg/s ⫺1,280 ⫾ 582 ⫺1,157 ⫾ 542 ⫺1,179 ⫾ 537 ⫺1,093 ⫾ 635
LVESP, mmHg
90 ⫾ 20
123 ⫾ 28
86 ⫾ 21
99 ⫾ 21§
78 ⫾ 25
69 ⫾ 22‡
69 ⫾ 22
BMCGS (PostCSD)
114 ⫾ 24*
1797 ⫾ 937*
⫺958 ⫾ 574
86 ⫾ 26
Values represent mean ⫾ SD % change in parameters from prestimulation value (n ⫽ 12). PostCSD values represent hemodynamic parameters after a 30-min
period of stabilization after removal of stellate ganglia. PreCSD represents hemodynamic values immediately before removal of the stellate ganglia. HR, heart
rate; dP/dtmax, dP/dtmin, maximum and minimum dP/dt; LVESP, left ventricular end-systolic pressure; BSGS, bilateral stellate ganglion stimulation; BMCGS,
bilateral middle cervical ganglion stimulation. *P value ⬍ 0.05 for % change from baseline (prestimulation). †P ⫽ 0.06 for % increase in dP/dtmax with BMCGS
compared with BSGS. ‡P ⫽ 0.02 for comparison of PreCSD vs. PostCSD. §P ⬍ 0.01 for comparison of BMCGS vs. BSGS.
A
glion stimulation (MCG stimulation: 24.7 ⫾ 3.5% vs. stellate
stimulation: 12.0 ⫾ 2.8%; P ⫽ 0.02; Fig. 6) The increase in
HR was also greater during bilateral MCG stimulation compared with bilateral stellate ganglion stimulation (Table 3),
LAD
Global ARI (ms)
400
350
300
250
PreCSD
PostCSD
444
432
421
409
397
385
374
362
350
339
327
315
ARI (ms)
P < 0.05
LV
Pre-CSD
LAD
RV
VT/VF Inducibility (%)
P < 0.05
0.05
B
RV
60
40
20
0
LV
Pre-CSD Post-CSD
Post-CSD
C
Post-CSD
Pre-CSD
500ms
500ms
III
II
V1
V1
V3
V3
RVD
RVD
RVP
RVP
Fig. 7. Effects of CSD and VT inducibility before and after CSD. A: epicardial global ARI from infarcted animals significantly increased with CSD (n ⫽ 12).
Blue dashed circle indicates region of the infarct on polar maps. B: inducibility of VT/VF was reduced after CSD in infarcted animals (n ⫽ 18: 12 were inducible
at baseline; of these 12 only 6 were inducible after CSD). C: example of VT induction with ventricular extrastimulus pacing. VT/VF was induced before CSD
with double extrastimuli at cycle lengths of 600/320/200 ms. After CSD, ERP was reached at an interval of 600/340 ms with double extrastimuli. Therefore, the
S2 stimulus was increased by 20 ms to 600/360 ms (to allow for consistent capture) and S3 was added and the interval reduced by 10 ms. The animal reached
ERP at 270 ms with triple extrastimuli (S3). Therefore, the S3 coupling interval was increased to 290 ms (to allow for consistent capture), and S4 was reduced
by 10 ms, starting at 600/360/290/400 ms. Despite reduction of S4 extrastimulus (triple extrastimulus testing) to a coupling interval of 200 ms, no ventricular
arrhythmias could be induced. RVD, distal poles of right ventricular endocardial catheter; RVP, proximal poles of right ventricular endocardial catheter.
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Thoracic sympathetic innervation in infarcted hearts. The
timeline for the experimental protocol in infarcted animals is
shown in Fig. 6. In infarcted animals, changes in ARI were
greater during MCG stimulation compared with stellate gan-
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ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
A
B
INFARCTED HEARTS
Post-CSD
BMCGS
P < 0.01
Percent Change in ARI (%)
P = 0.4
Global ARI (ms)
400
350
300
250
200
20
15
10
5
ARI (ms)
0
BMCGS
PreCSD
LAD
LV
LV
Apex
Apex
Post-CSD
BMCGS Post-CSD
PostCSD
D
Pre-CSD- Infarcted Hearts
1400
Infarcted Hearts
Post-CSD – Infarcted Hearts
80
1400
P=0.03
P=0.02
P=0.4
1200
1000
800
600
400
Tp-Te Interval (ms)
DOR (ms2)
1200
1000
800
600
400
200
200
BL
BMCGS
BL
BMCGS
P<0.05
P=0.01
60
40
20
Percent Change in Tp-Te (%)
C
DOR (ms2)
LAD
RV
RV
80
60
40
20
0
0
BL
BMCGS
Pre-CSD
BL
BMCGS
Post-CSD
PreCSD
PostCSD
Fig. 8. MCG stimulation and its effects before and after CSD on infarcted hearts. A: global ARI at baseline (BL) and during bilateral MCG stimulation (BMCGS)
after CSD and % change in ARI before vs. after CSD during BMCGS in infarcted hearts (n ⫽ 12). MCG stimulation decreased ARI despite CSD. B: examples
of polar maps at baseline and during MCG stimulation after CSD in infarcted hearts. Black dashed lines indicate course of left anterior descending coronary artery
(LAD). Blue dashed circle indicates region of scar. C: although MCG stimulation significantly increased DOR before CSD, this effect was mitigated after CSD
in infarcted hearts (n ⫽ 12). D: the prolongation in Tp-Te interval during MCG stimulation was reduced by CSD in infarcted hearts.
while the increase in LVESP was greater with stellate ganglion
stimulation. Finally, the rise in CS NE levels was similar
during bilateral MCG and bilateral stellate ganglion stimulation (Table 2).
CSD and residual sympathetic innervation in infarcted
hearts. In infarcted hearts, CSD led to a prolongation of global
ARI (pre-CSD: 385 ⫾ 17 ms vs. post-CSD: 392 ⫾ 17 ms; P ⬍
0.05; Fig. 7). CSD had no effect on HR or dP/dtmax. However,
a decrease in LVESP was observed after CSD in infarcted
hearts (P ⫽ 0.02; Table 3).
In 66.7% of MI animals (12/18), VT/VF was inducible
before CSD. After CSD, VT/VF was inducible in 6 of these 12
animals, reducing VT inducibility by 50% (P ⬍ 0.05; Fig. 7).
Of note, the six animals that were not inducible for VT/VF
before CSD remained noninducible after CSD.
Residual cardiac sympathetic pathways after CSD. In infarcted animals, global ARI continued to decrease during MCG
stimulation (Fig. 8). No significant differences in the effects of
MCG stimulation on hemodynamic parameters were observed
before vs. after CSD (Table 3).
Of note, CSD mitigated the increase in DOR during bilateral
MCG stimulation in infarcted animals. Before CSD, bilateral
MCG stimulation increased DOR by 356 ⫾ 222 ms2 (P ⬍
0.05; Fig. 8). However, after CSD the increase in DOR with
MCG stimulation was no longer significant (Fig. 8). Before
CSD, MCG stimulation increased Tp-Te interval from 44 ⫾ 4
ms to 68 ⫾ 7 ms (mean ⫾ SE) in infarcted hearts. After CSD,
MCG stimulation increased Tp-Te interval from 44 ⫾ 5 ms to
58 ⫾ 6 ms. Therefore, the percent increase in this interval
after CSD during MCG stimulation was significantly reduced (P ⬍ 0.05; Fig. 8). Given that premature ventricular
contractions that cause ventricular arrhythmias in infarcted
hearts often originate from the myocardium, we qualitatively assessed activation patterns during apical pacing in
five infarcted hearts (Fig. 9), which suggested improvement
in epicardial conduction/activation and decrease in functional block after CSD, or during MCG stimulation after
CSD, in two of the five infarcted hearts.
DISCUSSION
Major findings. In this study the MCG provided significant
innervation to the ventricles, and these sympathetic pathways
remained intact in normal and infarcted animals after CSD.
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BL
25
371
353
334
316
298
279
261
243
224
206
187
169
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
A
78
72
66
61
55
49
43
37
32
26
20
14
Pre-CSD
Post-CSD
AT (ms)
73
67
61
55
48
42
36
30
24
17
11
5
AT (ms)
BL Pre-CSD
BMCGS Pre-CSD
BL Post-CSD
BMCGS Post-CSD
Fig. 9. Modulation of propagation and activation time by CSD. A: polar maps
of activation time/sequence obtained during scar/apical pacing in this infarct
animal demonstrated a localized region at the septal border zone of the infarct
that was activated late as compared with the surrounding area. This area of
functional block (localized regions of late activation, delineated as “II”) before
CSD was no longer observed after CSD, and the entire area was activated more
homogeneously. B: polar maps of activation time/sequence during scar pacing
at baseline (BL) and during bilateral MCG stimulation (BMCGS) before and
after CSD in a different infarcted animal. During MCG stimulation, 2 localized
regions of late activation are seen at the border zone of the infarct, creating a
potential isthmus or area of slow conduction that could serve as the
substrate for a reentrant circuits. Both of these regions of late myocardial
activation are no longer observed during MCG stimulation after CSD. After
CSD, the entire region is more uniformly activated. Black dashed circle
indicates region of the infarct on polar maps.
Furthermore, bilateral CSD reduced VT inducibility acutely in
the setting of chronic MI, without compromising hemodynamic stability, a finding that can have implications for cardiomyopathy patients with recurrent ICD shocks. An important
mechanism behind the antiarrhythmic benefit of CSD in infarcted hearts was the mitigation of the effects of sympathetic
activation on DOR and on prolongation of Tp-Te interval, a
marker of sudden cardiac death.
Cardiac sympathetic innervation. Contribution of the MCG
to cardiac sympathetic innervation has previously been over-
looked. Cardiac neurons that fire in specific phases of the
cardiac cycle had been previously described in the MCG (7),
but the degree of functional sympathetic innervation to the
heart from the MCG was unknown. In this study, the effects of
bilateral MCG stimulation in normal hearts were similar to
those of bilateral stellate ganglion stimulation. However, in
infarcted animals, MCG stimulation led to significantly greater
effects on ARI and HR, while stellate ganglion stimulation had
greater effects on LVESP. Given multiple other fibers to the
head and neck that traverse through the MCG, removal of the
MCG, unlike the lower half of stellate ganglia, is not feasible
clinically. MCG stimulation continued to show significant
cardiac effects after hexamethonium infusion, suggesting that
the cardiac neural fibers from the MCG are postganglionic,
similar to the stellate ganglia.
Antiarrhythmic effects of CSD. Previous reports had shown
that left CSD can reduce ischemia-driven ventricular arrhythmias (30, 39). In this study, the rationale for performing
bilateral rather than just left CSD was driven by emerging
evidence in patients with structural disease and refractory
VT/VF. It has been noted that, unlike patients with channelopathies, case series of patients who undergo bilateral CSD for
refractory ventricular arrhythmias in the setting of structural
heart disease (i.e., MI) have greater VT-free survival compared
with patients who undergo left-side-only procedures (43). Furthermore, right stellate ganglion stimulation is also proarrhythmic, increasing DOR (50) and Tp-Te interval, an independent
marker of sudden cardiac death in patients (29, 33). Therefore,
in this model bilateral CSD was performed both to assess
hemodynamic stability after bilateral (rather than just leftsided) CSD and to assess VT inducibility acutely after bilateral
CSD. However, acute effects of CSD on ventricular arrhythmias in the setting of a chronic remodeled infarct were unknown. Furthermore, hemodynamic compromise with bilateral
CSD remained a concern (43). In this study, hemodynamic
parameters were not compromised, while arrhythmia inducibility decreased after CSD.
Although this study was performed in the swine model,
significant similarities between canine and human autonomic nervous systems exist. As in canines and in humans,
the sympathetic chain on each side consists of a superior
cervical, a middle cervical, and a stellate ganglion, followed
by a ganglion located at the level of each rib (20). As in the
canine model, sympathetic stimulation via the stellate ganglion increases DOR (45, 50). Direct and indirect sympathetic activation in humans increases DOR, similar to pigs
and dogs (44). Vagal nerve stimulation and decentralization
in pigs has effects similar to those in canines (6, 51).
Furthermore, we have shown that in the pig, similar to the
dog, intrinsic cardiac ganglia remodel in the setting of MI.
In addition, pig stellate ganglia show evidence of pathological neural remodeling similar to that in humans in the
setting of MI (1, 2). Of note, the cardiac neurons in the
MCG were first detected in the canine model (7). The fact
that the coronary circulation in the pig is more similar to that
in humans (than canine to human) is important in that the
scars that are generated in the porcine myocardial infarct
model are very similar to scars observed in humans with
ischemic cardiomyopathy, carrying the same electrical signature (25). In humans, as in pigs, the right and left stellate
ganglia provide significant innervation to the heart (20, 45).
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B
H401
H402
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
flow could play an important role in the antiarrhythmic
benefit of CSD. A framework for the current understanding
of the effect of CSD on cardiac neurotransmission via
afferent and efferent fibers is shown in Fig. 10.
Although CSD prolonged global ARI in infarcted animals,
this effect was not observed in normal animals. This may be
due to the heightened sympathetic tone and neural remodeling
that occurs in infarcted hearts (2), which can be improved by
interruption of efferent and afferent fibers through the stellate
ganglia and removal of these cardiac neurons.
It has been demonstrated both in this infarct model (26) and
in patients with ischemic and nonischemic cardiomyopathy
that scar regions are rarely composed of homogeneous and
dense fibrotic tissue (which would not give rise to any electrical signal) and contain many islands of live myocardium (24,
26, 32, 49). These regions of live myocardium or channels
within “scar” give rise to fractionated bipolar electrograms,
which have been shown to be good targets of catheter ablation
in patients with VT (19, 32, 40). However, these same scar
regions with intermingling myocytes have heterogeneous innervation (9, 44) that can lead to regions of delayed activation
and conduction block, allowing for reentry and ventricular
arrhythmias to occur (3, 34). In this study, we noted that in two
animals regions of slow activation along the septal border
zones of infarcts were improved after CSD, either at baseline
or during MCG stimulation, suggesting that CSD allowed for
more uniform cardiac activation, an antiarrhythmic effect.
More homogeneous activation could be either due to earlier
activation of “late” areas or, more likely, due to slower activation of the surrounding regions as a result of disruption of
sympathetic efferent fibers.
MCG stimulation after CSD. A theoretical concern with
performing bilateral CSD in patients with cardiomyopathy had
been the possibility of eliminating sympathetic pathways that
may be necessary for day-to-day activities and exercise. In this
study, efferent innervation from the MCG remained intact after
Brainstem
MCG
Fig. 10. Efferent and afferent cardiac sympathetic pathways.
Afferent fibers from the myocardium that traverse through
the MCG pass through the stellate ganglia before reaching
the spinal cord, and some of these pathways are interrupted
by CSD. In addition, preganglionic efferent fibers that pass
from the spinal cord through the stellate ganglia and to the
MCG and any postganglionic fibers that arise from the
stellate ganglia and innervate the myocardium are also interrupted. However, efferent postganglionic fibers from MCG
neurons to the myocardium remain intact despite CSD. Aff,
afferent neurons; Eff, efferent neurons; DRG, dorsal root
ganglion; IML, intermediolateral nucleus; DH, dorsal horn of
the spinal cord.
Stellate
DRG
Eff
DH
Eff
IML
Aff
Aff
DH
IML
HEART
DH
IML
CSD
Pre-ganglionic efferent sympathetic fibers
Post-ganglionic efferent sympathetic fibers
Afferent sympathetic fibers
Intraganglionic Information Processing
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Sympathetic
Chain
Spinal Cord
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As in canines, the right stellate ganglion provides predominant innervation to the anterior aspect of the heart and the
left stellate ganglion provides innervation to the posterior/
dorsal aspect of the heart (45, 52). As in canines, sympathetic stimulation via the stellate ganglia in pigs increases
DOR and predisposes to arrhythmias (28, 50).
In addition to interrupting efferent fibers, some of the
beneficial effects of CSD are likely due to interruption of
afferent neurotransmission. Cardiac sympathetic afferent
fibers exist throughout the cardiac chambers and sense
mechano-chemical stimuli (22). Disruption of these afferent
fibers reduces sympathetic outflow and has been shown to
decrease the number of ectopic beats that occur with brief
episodes of ischemia (36). Ventricular pacing leads to activation of cardiac mechanoreceptors and increased sympathetic tone, and alteration of processing through the intrinsic
cardiac ganglia can be observed (18, 31). Afferent fiber
activation subsequently increases sympathetic efferent outflow (37) and can explain the shorter ARIs that were
observed with apical ventricular pacing compared with right
atrial pacing before CSD, despite a fixed pacing cycle
length. This effect was eliminated after CSD. Therefore, a
portion of the antiarrhythmic benefit of CSD is likely due to
interruption of afferent neurotransmission, which then alters
subsequent efferent neurotransmission via the stellate and
middle cervical ganglia. Sympathetic activation during VT
inducibility testing (18, 35, 42), which by its nature involves
ventricular pacing, is reduced by CSD in infarcted hearts,
leading to fewer observed arrhythmias. In fact, it has been
shown that sympathetic afferent responses to noxious stimuli are enhanced in heart failure dogs and increase renal
sympathetic outflow more than in normal animals (48).
Furthermore, chemical cardiac sympathetic deafferentation
by epicardial application of resiniferatoxin decreases cardiac sympathetic nerve activity and attenuates cardiac remodeling in rats with heart failure (47). Therefore, reduction
in afferent transduction leading to decreased efferent out-
ANTIARRHYTHMIC MECHANISM OF BILATERAL STELLECTOMY
GRANTS
This study was supported by National Heart, Lung, and Blood Institute
(NHLBI) Grant 1DP2 HL-132356 and American Heart Association Award
11FTF755004 to M. Vaseghi and NHLBI Grant R01 HL-084261 to K.
Shivkumar.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
T.I., K.Y., D.H., K.N., and M.V. performed experiments; T.I., K.Y., and
M.V. analyzed data; T.I., K.Y., and M.V. interpreted results of experiments; T.I. and M.V. prepared figures; T.I. and M.V. drafted manuscript;
K.Y., D.H., K.N., K.S., and M.V. approved final version of manuscript;
D.H., K.S., and M.V. edited and revised manuscript; M.V. conceived and
designed research.
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CSD, and CSD did not lead to any hemodynamic compromise
in the porcine model.
Stellate ganglion stimulation has been reported to increase DOR and Tp-Te interval (45, 50). Tp-Te interval
represents both transmural and whole heart DOR and increases the risk of sudden cardiac death (8, 27, 33). In this
study, MCG stimulation also increased DOR and Tp-Te
interval in infarcted hearts. Importantly, CSD mitigated the
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compromise is reassuring.
Limitations. Electrograms were recorded only from ventricular epicardium. Therefore, intramural and endocardial
effects were not assessed. This study was performed in a
porcine model, and given interspecies differences direct
interpolation to humans requires additional studies. In addition, isoflurane, which can suppress autonomic activity,
was used for general anesthesia during the surgical portion
of the protocol. However, anesthesia was switched to
␣-chloralose during the stimulation and CSD portions of the
protocol. In addition, ARI and Tp-Te interval were not
corrected for increases in HR. Therefore, increases in Tp-Te
interval observed with stimulation are likely a conservative
estimate of the actual effects. Given different stimulation
currents to achieve the same hemodynamic threshold, direct
comparison of parameters in MI vs. normal hearts was not
performed. However, stimulation currents for right and left
stellate ganglia vs. MCG were similar. Finally, direct comparison of ARI values at baseline or after CSD in infarcted
compared with normal hearts cannot be made, as normal
animals did not undergo a sham MI procedure, did not have
VT inducibility testing, and had an additional bilateral
stellate ganglion and MCG stimulation where the time
courses of effects of bilateral stellate ganglion stimulation
and MCG stimulation were compared. Finally, VT inducibility was not tested during MCG stimulation. However,
VT inducibility, by the nature of its ventricular pacing, does
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the beneficial effects of CSD are most influential during a
state of elevated sympathetic tone.
Conclusions. Both MCG and stellate ganglia contribute
significantly to cardiac sympathetic innervation. In addition,
VT inducibility in animals with chronic MI is significantly
reduced by bilateral CSD, even acutely. A mechanism for this
benefit is the improvement in the increase in DOR and Tp-Te
interval prolongation observed with sympathetic activation.
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