Download Cardiac Sympathetic Innervation Via the Middle Cervical and

Articles in PresS. Am J Physiol Heart Circ Physiol (December 23, 2016). doi:10.1152/ajpheart.00644.2016
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CARDIAC SYMPATHETIC INNERVATION VIA THE MIDDLE CERVICAL
AND STELLATE GANGLIA AND ANTI-ARRHYTHMIC MECHANISM OF
BILATERAL STELLECTOMY
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Running Title: Anti-arrhythmic Mechanism of Bilateral Stellectomy
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Tadanobu Irie,1,2* Kentaro Yamakawa,2* David Hamon,1,2 Keijiro Nakamura,1,2 Kalyanam
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Shivkumar,1,2 Marmar Vaseghi1,2
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UCLA Cardiac Arrhythmia Center & 2 Neurocardiology Research Center of Excellence,
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Los Angeles, CA
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*These authors contributed equally
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Drs. Irie created the infarct model, helped perform the terminal experiments, assisted in data analysis
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and interpretation, and drafted the manuscript. Dr. Yamakawa performed the terminal experiments,
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data analysis, and interpretation. Drs. Hamon and Nakamura participated in creating the infarct model
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and performing the terminal experiments. Dr. Shivkumar participated in the design of the study, helped
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with funding of the study, and edited and revised the manuscript. Dr. Vaseghi designed and funded the
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study, assisted in performing the experiments, data analysis and interpretation, and drafted and
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revised the manuscript.
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Address for Correspondence
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Marmar Vaseghi, MD, PhD
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UCLA Cardiac Arrhythmia Center,
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100 Medical Plaza, Suite 660,
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Los Angeles, CA 90095
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Tel:+1-310-206-2235
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Fax:+1-310-825-2092
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Email: [email protected]
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Copyright © 2016 by the American Physiological Society.
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ABSTRACT
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Cardiac sympathetic denervation, CSD, is reported to reduce burden of ventricular
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tachy-arrhythmias (VT/VF) in cardiomyopathy patients, but the mechanisms behind this
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benefit are unknown. In addition, the relative contribution to cardiac innervation of the middle
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cervical ganglia (MCG), which may contain cardiac neurons, and is not removed during this
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procedure, is unclear.
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the heart via the MCG vs. stellate ganglia, assess effects of bilateral CSD on cardiac function
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and VT/VF, and determine changes in cardiac sympathetic innervation after CSD to elucidate
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mechanisms of benefit in 6 normal and 18 infarcted pigs.
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hemodynamic parameters were evaluated at baseline, during bilateral stellate and during
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bilateral MCG stimulation in 6 normal and 12 infarcted animals. Bilateral CSD (removal of
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bilateral stellates and T2 ganglia) was then performed, and MCG stimulation repeated. In
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addition, in 18 infarcted animals VT/VF inducibility was assessed pre- and post-CSD.
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infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response
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than stellate ganglia stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in
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infarcted hearts and prolonged global activation recovery interval. CSD mitigated effects of
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MCG stimulation on dispersion of repolarization and T-peak to T-end interval in infarcted
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hearts, without causing hemodynamic compromise. This data demonstrate that the MCG
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provides significant cardiac sympathetic innervation before CSD and adequate sympathetic
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normal after CSD, maintaining hemodynamic stability.
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inducibility by improving electrical stability in infarcted hearts in the setting of sympathetic
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activation.
The purpose of this study was to compare sympathetic innervation of
Electrophysiological and
In
Bilateral CSD reduces VT/VF
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NEW AND NOTEWORTHY
Sympathetic activation in myocardial infarction leads arrhythmias and worsens heart
failure. Bilateral cardiac sympathetic denervation reduces VT/VF 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 ganglia is not interrupted.
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KEYWORDS
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Autonomic;
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sympathetic nervous system
cardiac
sympathetic
denervation;
stellectomy,
ventricular
arrhythmias,
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INTRODUCTION
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Myocardial infarction (MI) increases risk of sudden cardiac death due to ventricular
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tachy-arrhythmias (VT/VF),(13) by causing pathological cardiac (16, 34, 41) and neural
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remodeling.(15, 44, 53)
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increases T-peak to T-end (Tp-Te) interval, a marker of sudden cardiac death (8, 33) and
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increases dispersion of repolarization, predisposing to VT/VF.(27, 44, 45, 50) Left cardiac
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sympathetic denervation (CSD) has been reported to decrease burden of VT/VF in patients
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with hereditary channelopathies, including long QT syndrome and catecholaminergic
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polymorphic ventricular tachycardia, who have structurally normal hearts.(4, 17, 38) In a
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small series of patients with structural heart disease, bilateral CSD has shown promise in
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reducing burden of internal cardioverter defibrillator (ICD) shocks. This study also suggested
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that bilateral CSD may lead to a greater ICD shock free survival compared to left CSD in
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patients with cardiomyopathy.(43) However, electrophysiological mechanisms behind the
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reduction in life-threatening arrhythmias with CSD are not clear. In addition, it is unknown how
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much of cardiac sympathetic innervation, that may be required for beat-to-beat function, is
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preserved after bilateral CSD. The middle cervical ganglia (MCG), located anatomically
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superior to the stellate ganglia, have been reported to contain cardiac sympathetic neurons,(7,
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electrophysiological effects have not been characterized. The purpose of this study was to
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delineate (1) sympathetic innervation of the heart via the MCG compared to the stellate
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ganglia (2) electrophysiological and anti-arrhythmic effects of CSD, including VT inducibility,
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and (3) alterations in functional cardiac sympathetic innervation after CSD and its
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anti-arrhythmic mechanisms in a porcine model.
and
could
provide
Sympathetic activation via the right or left stellate ganglion
sympathetic
innervation
after
CSD.
However,
their
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METHODS
Study procedures were approved by UCLA Institutional Animal Research Committee
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and performed in compliance with the National Institutes of Health Guide for the Care and
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Use of Laboratory Animals.
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Creation of Myocardial Infarcts
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Eighteen Yorkshire pigs were sedated (telazol 6-10 mg/kg and fentanyl 2-5 μg/kg),
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intubated, and placed under general anesthesia with inhaled isoflurane (0.5-1.5%). After
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femoral arterial access was obtained using an 8F sheath, an Amplatz guide catheter (Boston
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Scientific, Marlborough, MA) was advanced over a J tipped guide wire under fluoroscopic
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guidance and used to cannulate the left main coronary artery from the left femoral artery. A
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coronary angiogram was performed to delineate the branches of the left anterior descending
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coronary artery. A 3 mm luminal angioplasty balloon (Armada 35 PTA, Abbott Vascular,
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Temecula, CA) was advanced past the first diagonal branch of the left anterior descending
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artery over a 0.014 inch coronary guide wire (Balance Middle Weight wire, Abbott Vascular,
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Temecula, CA) and inflated. Polystyrene microspheres (5.0-7.5 ml, Polysciences, Inc.
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Warrington, PA) were injected through the lumen of the percutaneous balloon catheter.(26)
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Repeat coronary angiography after microsphere injection showed confirmed poor blood flow
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in the LAD after the first diagonal branch. Continuous electrocardiogram (ECG) monitoring
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was performed. ECG changes including ST segment elevation and or T wave inversions were
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also used to confirm myocardial infarction acutely. If sustained VT/VF was observed,
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resuscitation with chest compressions and external direct current cardioversion was
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performed. Animals were then extubated and monitored until they could ambulate without
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assistance.
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Surgical Preparation
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Four to six weeks after MI, 18 infarcted (48 ± 2 kg) and six normal animals (43 ± 1
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kg) were sedated (telazol 6-10 mg/kg and fentanyl 2-5 μg/kg) and placed under general
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anesthesia with isoflurane (0.8-1.5%). Normal animals had not undergone a percutaneous
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interventional procedure prior to terminal experiments. Median sternotomy was performed
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and isolation of bilateral stellate ganglia and T2 thoracic ganglia (all animals) and bilateral
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MCG (12 of 18 animals) were performed. Presence and extent of scar on the epicardium was
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assessed in infarcted animals grossly, figure 1, as well as by using bipolar voltage
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measurements using a 2-2-2 duodecapolar catheter (2-2-2 mm spacing, St. Jude Medical, St.
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Paul, MN). Regions with a voltage less than 0.5 mV were defined as scar, those with voltage
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of 0.5 to 1.5 mV were defined as border zone (BZ), and electrodes overlying regions with
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voltage greater than 1.5mV were defined as viable/normal.(14, 23) The location and extent of
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infarct was marked on the heart.
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subclavian artery, at the inlet of the thorax, figure 1. After completion of the surgical portion of
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the procedure, isoflurane was discontinued, and an intravenous infusion of α-chloralose
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(10-30 mg/kg/h) was begun.(5, 10, 11) During anesthesia with both α-chloralose and
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isoflurane, heart rate as well as jaw tone and eye blink reflexes were monitored every 10-15
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minutes to ensure adequate sedation.
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Stellate and Middle Cervical Ganglia Stimulation
The MCG were identified often above and behind the
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Bipolar needle electrodes (figure 1) were used for bilateral stellate ganglia
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stimulation and bilateral middle cervical ganglia stimulation using a Grass Stimulator (Model
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S88, Grass Technologies, Warwick, RI) in both infarcted (n =12) and normal (n = 6) animals.
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Threshold was defined as current needed to increase heart rate (HR) or systolic blood
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pressure by 10% (at 4Hz, 4 ms).
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Stimulation was performed at 1.5 times threshold for 30 seconds. In normal animals,
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the stimulation current used for right stellate ganglion was 2.4±0.5 mA and for the right MCG
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was 2.3±0.4 mA. The stimulation current used for the left stellate ganglion was 5.6±0.8 mA
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and for the left MCG was 6.0±0.7 mA in normal animals. For infarcted animals, the stimulation
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current used for the right stellate ganglion was 6.7±1.0 mA and for the right MCG was 5.9±1.2
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mA; the current for left stellate ganglion stimulation was 9.8±1.0 mA and for left MCG was
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10.0±1.0 mA. In normal animals, a second stellate and MCG stimulation was performed prior
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to CSD for 60 seconds and electrophysiological effects were compared at 5, 10, 15, 20, 30,
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45, and 60 seconds. A 30-minute period was allowed for return of hemodynamic parameters
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to baseline in between stimulations. The timeline for the experimental protocol in normal
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animals is shown in figure 2.
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Hemodynamic and Electrocardiogram Recordings
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Hemodynamic parameters were continuously recorded with a 12-pole conductance
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pressure catheter in the left ventricle (LV), connected to a MPVS Ultra® Pressure Volume
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Loop System (Millar Instruments, Houston, TX). ECG was continuously obtained using the
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GE Cardiolab System (GE Healtcare). Tp-Te interval was assessed in the inferior leads with
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the clearest T wave. Tp-Te interval was assessed in the inferior leads with the clearest T wave
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off-line manually from the electrocardiograms obtained from the Cardiolab System at 400 mm/sec
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paper speed.
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peak of the T wave was visually determined, and the end of the T wave was defined as the
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intersection of the tangent to the slope of the T wave and the isoelectric line, when not followed by
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a U wave, figure 1. If a U wave followed the T wave, the off-set of the T-wave was measured as
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the nadir between the T and U waves. This is a similar to what has been described in the literature.
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(29, 50)
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Bilateral Cardiac Sympathetic Denervation
Tp-Te interval was measured from the peak of T wave to the end of T wave. The
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Bilateral CSD was performed in 18 infarcted and 6 normal animals after isolation of
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bilateral stellate and T2 thoracic ganglia. T3 and T4 thoracic ganglia were not removed as it
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has been previously shown that cardiac fibers from these ganglia traverse through the
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stellate and T2 ganglia before reaching the heart.(12) The lungs on each side were retracted,
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the sympathetic chain again identified, and its connections to the spinal cord and
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cardiopulmonary nerves were transected. Both stellate ganglia and T2 thoracic ganglia were
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removed. A 30-minute stabilization period after CSD was allowed prior to repeat stimulation
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or inducibility testing. VT/VF inducibility was tested pre- and post-CSD.
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Inducibility Testing for Ventricular Tachy-arrhythmias
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In 18 infarcted hearts, programmed ventricular stimulation up to triple extra-stimuli to
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a minimum coupling interval of 200 ms or effective refractory period was performed before
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and after CSD first from the right ventricular endocardium at the mid to apical septum using
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an endocardial quadripolar electrophysiology catheter connected to a MicroPace stimulator
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(MicroPace EP Inc. Santa Ana, CA). Current was set at two times the ventricular capture
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threshold in each animal and pulse duration of 1 ms. If VT/VF was not induced from the RV
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endocardium at baseline pre-CSD, a second site on the LV epicardium close to the scar was
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used pre-CSD. The same or a very similar site was used for induction of VT/VF post-CSD
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that had been used to induce VT/VF pre-CSD. The induction protocol was as follows: an
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extra-stimulus was placed after 8 beats of drive cycle length (at 500 ms) at an interval of 400
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ms (S2). The premature extra-stimulus interval (S2) was reduced by 10 ms until either an
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interval of 200 ms or effective refractory period (ERP) was reached or VT/VF was induced.
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If VT/VF was not induced, then, S2 was fixed at 20 ms above the effective refractory period or
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at 220 ms (if ERP was < 200 ms), and a second premature extra-stimulus (S3) was added at
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an interval of 400 ms. The S3 interval was then reduced by 10 ms until an S2-S3 interval of
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200 ms, or effective refractory period was reached, or VT/VF was induced. Finally, if no
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VT/VF was induced, then S3 interval was set at 220 ms (if ERP was < 200 ms) or 20 ms
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above effective refractory period, and an S4 interval (triple extra-stimulus) added at an S3-S4
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interval of 400 ms. This S4 interval was then reduced by 10 ms until a coupling interval of 200
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ms or effective period was reached, or VT/VF was induced. Inducibility was defined as
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hemodynamically tolerated VT that lasted greater than 30 seconds or that degenerated into
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VF requiring direct cardioversion.
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Measurement of Norepinephrine Levels
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Norepinephrine (NE) levels in the inferior vena cava and coronary sinus (CS) were
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measured to confirm adequate ganglia stimulation. Venous blood was obtained from a
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luminal catheter inserted in the IVC, superior to the adrenal veins and close to the right atrium.
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CS blood was obtained by cannulation of the CS with a luminal catheter (St. Jude Medical, St.
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Paul, MN) from the right external jugular vein. Blood samples at baseline and in the last 5
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seconds of stellate ganglia and MCG stimulation pre-CSD were immediately centrifuged
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(3000 rpm, 15 minutes) to separate the plasma portion. Quantification of NE was performed
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using an ultrasensitive enzyme linked immunoassay (ELISA, BA E-5200, sensitivity 1.3 pg/ml,
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Labor Diagnostika Nord GmbH & Co.KG, Nordhorn, Germany) and an ELISA microplate
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reader (Fisher Scientific, Waltham, MA).
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ARI Recordings
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In 12 infarcted and 6 normal animals, detailed electrophysiological mapping was
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performed. A 56-electrode sock (figure 1) was placed over the ventricles to assess activation
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recovery interval (ARI), a surrogate of local action potential duration. Unipolar electrograms
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were recorded (0.05-500 Hz) using the GE Cardiolab System. ARIs were calculated with
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customized software (Scaldyn, University of Utah, Salt Lake City, UT) as previously
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described.(44, 46) Briefly, activation time (AT) was defined as the interval from electrogram
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onset to most negative dV/dt of the activation wave, and repolarization time (RT) was defined
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as the interval from electrogram onset to the most positive dV/dt of the repolarization wave.
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ARI was defined as the difference between RT and AT. Map3D software (University of Utah)
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was used to map epicardial pattern of activation and ARI using a sock-electrode polar map
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template, figure 1F. Global dispersion of repolarization (DOR) was calculated as the variance
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of ARIs recorded across all epicardial electrodes.
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In this manuscript, anterior refers to ventral and posterior refers to dorsal aspect of
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the heart. In normal animals, mean ARIs in the following regions were analyzed based on
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electrode location: LV apex, LV anterior, LV lateral, LV posterior wall and right ventricular (RV)
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anterior, lateral, posterior wall, and RV outflow tract. A median of 3 electrodes (range 2-4) per
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region was used for regional ARI and AT analysis.
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Atrial and Ventricular Pacing
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To evaluate effect of CSD on ARI during ventricular pacing compared to atrial pacing,
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ventricular pacing was performed at baseline and during MCG stimulation before and after
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CSD (pacing cycle length = 400 ms or 500 ms, depending on HR during stimulation) in 6
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normal and 5 infarcted animals. To compare differences to ventricular pacing, right atrial
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pacing at the same cycle length was performed in normal animals at baseline and during
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BMCGS, pre- and post-CSD. In addition, Map3D software (University of Utah, Salt Lake City,
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UT, http://www.sci.utah.edu/cibc-software/map3d.html) was used to map epicardial pattern of
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activation and ARI during scar pacing in 5 infarcted hearts. The template, with sock electrode
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locations, used for creation of these polar maps is shown in figure 1.
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Pre-ganglionic vs. Post-ganglionic Neural Fibers Within the MCG
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To evaluate presence of pre- vs. post-ganglionic fibers within the MCG in normal
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animals after CSD, bilateral MCG stimulation was repeated after infusion of hexamethonium,
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a nicotinic receptor blocker. Right vagal nerve stimulation (VNS) was also performed pre and
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post hexamethonium infusion to ensure nicotinic receptor blockade, as vagal efferent
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parasympathetic fibers are known to be preganglionic. The right cervical vagal trunk was
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isolated via a lateral neck cut-down and bipolar needle electrodes (Cyberonics, Houston, TX)
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attached to a Grass Stimulator used for right VNS (10 Hz, 1 ms).
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the current at which HR decreased by 10%, and stimulation performed at 1.2 times threshold
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for 20 seconds, before and after hexamethonium. Hexamethonium was infused for 30
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minutes (0.025-0.2 mg/kg/min, dose titrated by response to right VNS in each animal).
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Statistical Analysis
Threshold was defined as
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Unless specified otherwise, data are presented as mean±standard error (SE). Global
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ARI was calculated as the mean ARI across all 56 electrodes. Global dispersion of
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repolarization (DOR) was calculated as the variance in ARIs across all 56 electrodes. For
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comparison of paired variables, Wilcoxon signed-rank or paired t-test was used was used.
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Sample size of infarcted animals was driven by the assumption of a 40% reduction in VT/VF
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inducibility after CSD with 80% power to detect this reduction at alpha of 0.05. McNemar test
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was used to compare VT inducibility before and after CSD. Sample size of normal animals
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was driven by 80% power to detect a 10% difference in the effects of MCG vs. stellate ganglia
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stimulation on global ARI in the same animal at an alpha of 0.05. The Mann-Whitney test was
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used for comparison of continuous variables in different groups. Percentage change in
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regional ARIs for stellate ganglia vs. MCG stimulation were analyzed using repeated
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measure ANOVA after controlling for a false discovery rate at 5%. SPSS (version 22, IBM,
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Armonk, NY) was used for statistical analysis. P<0.05 was considered statistically significant.
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RESULTS
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Thoracic Sympathetic Innervation in Normal Hearts
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Timeline for the experimental protocol in normal animals is shown in figure 2. In
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normal hearts bilateral stellate ganglia and bilateral MCG stimulation significantly increased
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HR, maximum dP/dt, and left ventricular end-systolic pressure Table 1. Comparison of
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bilateral stellate ganglia to bilateral MCG stimulation demonstrated no differences in the HR
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or maximum dP/dt increase. However, bilateral stellate ganglia stimulation had a greater
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effect on left ventricular end-systolic pressures (LVESP) than bilateral MCG stimulation.
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Coronary sinus NE levels increased in a similar fashion during bilateral stellate and bilateral
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MCG stimulation compared to pre-stimulation values, Table 2.
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Both bilateral stellate and MCG stimulation decreased epicardial ARI, figure 2. There
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was no significant difference in the time course of ARI shortening during the 60 seconds of
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stimulation between the stellate ganglia and MCG, figure 3, and no differences in regional
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ARIs were detected between bilateral stellate and bilateral MCG stimulation figure 3.
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Compared to right atrial pacing, LV apical pacing at baseline and during MCG
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stimulation at the same cycle length led to significantly shorter epicardial ARIs, P<0.05,
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suggesting that ventricular pacing alone led to cardiac sympathetic activation, figure 3.
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CSD and Residual Sympathetic Innervation in Normal Hearts
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CSD did not cause hemodynamic deterioration in normal hearts, table 1.
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global ARI was observed before compared to after CSD, figure 4.
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No difference in
MCG continued to exert significant sympathetic effects after CSD. Global ARI
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continued to decrease during MCG stimulation after CSD, figure 4.
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stimulation after CSD on HR and dP/dt max were unchanged compared to before CSD, table
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1. Of note, comparison of atrial to ventricular pacing at the same cycle length showed that the
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differences in ARI shortening between RA pacing and LV pacing were no longer significant
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after CSD, with or without MCG stimulation, figure 3. DOR and Tp-Te interval, which
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increased during MCG stimulation, were unaffected by CSD in normal hearts, figure 4.
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Furthermore, CSD had no effect on activation time (pre-CSD: baseline 26.1±1.5 ms vs. MCG
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stimulation 30.4±4.1 ms, P=0.3, post-CSD: baseline 26.1±1.1 ms vs. MCG stimulation
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28.2±1.5 ms, P=0.2).
Effect of bilateral MCG
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To evaluate presence of preganglionic fibers within the MCG, response to
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hexamethonium was evaluated. Right VNS was also performed to assure adequate nicotinic
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receptor blockade.
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hexamethonium, figure 5. After hexamethnoium infusion, there was no change in global ARI
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during right VNS. However, effects of MCG stimulation after hexamethonium were
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unchanged, suggesting presence of predominantly post-ganglionic sympathetic fibers in the
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MCG, figure 5.
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Thoracic Sympathetic Innervation in Infarcted Hearts
Global ARI significantly increased during right VNS prior to
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Timeline for the experimental protocol in infarcted animals is shown in figure 6. In
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infarcted animals, changes in ARI were greater during MCG stimulation compared to stellate
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ganglia stimulation (MCG stimulation: 24.7±3.5% vs. stellate stimulation: 12.0±2.8%), P=0.02,
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figure 6. The increase in HR was also greater during bilateral MCG stimulation compared to
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bilateral stellate gangila stimulation, table 3, while the increase in LVESP was greater with
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stellate ganglia stimulation. Finally, the rise in coronary sinus NE levels was similar during
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bilateral MCG compared to bilateral stellate ganglia stimulation, table 2.
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CSD and Residual Sympathetic Innervation in Infarcted Hearts
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In infarcted hearts, CSD led to a prolongation of global ARI (pre-CSD: 385±17 ms vs.
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post-CSD: 392±17 ms, P<0.05), figure 7. CSD had no effect on HR or dP/dt max. However, a
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decrease in LVESP was observed after CSD in infarcted hearts, P=0.02, table 3.
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In 66.7% of MI animals (12/18), VT/VF was inducible prior to CSD. After CSD, VT/VF
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was inducible in 6 of these 12 animals, reducing VT inducibility by 50% (P<0.05), figure 7. Of
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note, the 6 animals, which were not inducible for VT/VF before CSD, remained non-inducible
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after CSD.
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Residual Cardiac Sympathetic Pathways After CSD
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In infarcted animals, global ARI continued to decrease during MCG stimulation, figure 8. No
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significant differences in the effects of MCG stimulation on hemodynamic parameters were
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observed pre vs. post-CSD, table 3.
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Of note, CSD mitigated the increase in DOR during bilateral MCG stimulation in
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infarcted animals. Before CSD, bilateral MCG stimulation increased DOR by 356±222 ms2,
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P<0.05, figure 8.
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longer significant, figure 8. Before CSD, MCG stimulation increased Tp-Te interval from 44±4
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ms to 68±7 ms (mean±SE) in infarcted hearts. After CSD, MCG stimulation increased Tp-Te
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interval from 44±5 ms to 58±6 ms. Therefore, the percentage increase in this interval after
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CSD during MCG stimulation was significantly reduced, P<0.05, figure 8. Given that
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premature ventricular contractions that cause ventricular arrhythmias in infarcted hearts often
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originate from the myocardium, we qualitatively assessed activation patterns during apical
However, after CSD the increase in DOR with MCG stimulation was no
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pacing in 5 infarcted hearts, figure 9, which suggested improvement in epicardial
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conduction/activation and decrease in functional block after CSD, or during MCG stimulation
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after CSD, in two of the five infarcted hearts.
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DISCUSSION
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Major Findings
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In this study the MCG provided significant innervation to the ventricles, and these
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sympathetic pathways remained intact in normal and infarcted animals after CSD.
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Furthermore, bilateral CSD reduced VT inducibility acutely in the setting of chronic MI,
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without compromising hemodynamic stability, a finding that can have implications for
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cardiomyopathy patients with recurrent ICD shocks. An important mechanism behind the
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anti-arrhythmic benefit of CSD in infarcted hearts was the mitigation of the effects of
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sympathetic activation on DOR and on prolongation of Tp-Te interval, a marker of sudden
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cardiac death.
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Cardiac Sympathetic Innervation
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Contribution of the MCG to cardiac sympathetic innervation has been previously
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overlooked. Cardiac neurons that fire in specific phases of the cardiac cycle had been
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previously described in the MCG.(7) But the degree of functional sympathetic innervation to
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the heart from the MCG was unknown. In this study, effects of bilateral MCG stimulation in
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normal hearts were similar to bilateral stellate ganglia stimulation. However, in infarcted
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animals, MCG stimulation led to significantly greater effects on ARI and HR, while stellate
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ganglia stimulation had greater effects on LVESP. Given multiple other fibers to the head and
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neck that traverse through the MCG, removal of the MCG, unlike the lower half of stellate
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ganglia, is not feasible clinically. MCG stimulation continued to show significant cardiac
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effects after hexamethonium infusion, suggesting that the cardiac neural fibers from the MCG
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are post-ganglionic, similar to the stellate ganglia.
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Anti-Arrhythmic Effects of CSD
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Previous reports had shown that left CSD can reduce ischemia driven ventricular
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arrhythmias.(30, 39) In this study, the rationale for performing bilateral rather just left CSD
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was driven by emerging evidence in patients with structural disease and refractory VT/VF. It has
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been noted that unlike patients with channelopathies, case series of patients who undergo
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bilateral CSD for refractory ventricular arrhythmias in the setting of structural heart disease (i.e.
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myocardial infarction) have greater ventricular tachycardia free survival compared to those
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patients who undergo left sided only procedures.(43) Furthermore, right stellate ganglion
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stimulation is also pro-arrhythmic, increases dispersion of repolarization(50) and T-peak to T-end
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interval, an independent marker of sudden cardiac death in patients.(29, 33), Therefore, in this
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model, bilateral CSD was performed both to assess hemodynamic stability after bilateral (rather
373
just left sided CSD) and to assess VT inducibility acutely after bilateral CSD. However, acute
374
effects of CSD on ventricular arrhythmias in the setting of a chronic remodeled infarct were
375
unknown. Furthermore, hemodynamic compromise with bilateral CSD remained a
376
concern.(43) In this study, hemodynamic parameters were not compromised while arrhythmia
377
inducibility decreased after CSD.
378
Although this study was performed in the swine model, significant similarities
379
between canine and human autonomic nervous system exist. As in canines and in humans,
380
the sympathetic chain on each side consists of a superior cervical, a middle cervical, and a
381
stellate ganglion, followed by a ganglion located at the level of each rib.(20) Like the canine model
382
sympathetic stimulation via the stellate ganglion increase dispersion of repolarization.(45, 50)
383
Direct and indirect sympathetic activation in humans increases dispersion of repolarization,
384
similar to pigs and dogs.(44) Vagal nerve stimulation and decentralization in pigs has similar
385
effects to canines.(6, 51) Furthermore, we have shown that in the pig, similar to the dog, intrinsic
386
cardiac ganglia remodels in the setting of myocardial infarction. In addition, pig stellate ganglia
387
show evidence of pathological neural remodeling similar to humans in the setting of myocardial
15
388
infarction.(1, 2) Of note, the cardiac neurons in the MCG were first detected in the canine
389
model.(7) The fact that coronary circulation in the pig is more similar to humans (than canines to
390
humans) is important in that the scars that are generated in the porcine myocardial infarct model
391
are very similar to scars observed in humans with ischemic cardiomyopathy, carrying the same
392
electrical signature.(25) In humans, as in pigs, the right and left stellate ganglia provide significant
393
innervation to the heart, which is also true of humans.(20, 45) Like canines, the right stellate
394
ganglion provides predominant innervation to the anterior aspect of the heart and left stellate
395
ganglion provides innervation to the posterior/dorsal aspect of the heart.(45, 52) Like canines,
396
sympathetic stimulation via the stellate ganglia in pigs increases dispersion of repolarization and
397
predisposes to arrhythmias.(28, 50)
398
In addition to interrupting efferent fibers, some of the beneficial effects of CSD are
399
likely due to interruption of afferent neurotransmission. Cardiac sympathetic afferent fibers
400
exist throughout the cardiac chambers, and sense mechano-chemical stimuli.(22) Disruption
401
of these afferent fibers reduces sympathetic outflow and has been shown to decrease the
402
number of ectopic beats that occur with brief episodes of ischemia.(36) Ventricular pacing
403
leads to activation of cardiac mechano-receptors, increased sympathetic tone, and alteration
404
processing through the intrinsic cardiac ganglia can be observed.(18, 31) Afferent fiber
405
activation subsequently increases sympathetic efferent outflow,(37) and can explain the
406
shorter ARIs that were observed with apical ventricular pacing compared to right atrial pacing
407
before CSD, despite a fixed pacing cycle length. This effect was eliminated after CSD.
408
Therefore, a portion of the anti-arrhythmic benefit of CSD is likely due to interruption of
409
afferent neurotransmission, which then alters subsequent efferent neurotransmission via the
410
stellate and middle cervical ganglia. Sympathetic activation during VT inducibility testing, (18,
411
35, 42) which by its nature involves ventricular pacing, is reduced by CSD in infarcted hearts,
412
leading to less observed arrhythmias. In fact, it has been shown that sympathetic afferent
413
responses to noxious stimuli are enhanced in heart failure dogs and increase renal
16
414
sympathetic outflow more than normal animals.(48) Furthermore, chemical cardiac
415
sympathetic de-afferentation using epicardial application of resiniferatoxin decreases cardiac
416
sympathetic nerve activity and attenuates cardiac remodeling in rats with heart failure.(47)
417
Therefore, reduction in afferent transduction leading to decrease efferent outflow could play
418
an important role in the anti-arrhythmic benefit of CSD. A framework for the current
419
understanding of the effect of CSD on cardiac neurotransmission via afferent and efferent
420
fibers is shown in figure 10.
421
Although CSD prolonged global ARI in infarcted animals, this effect was not
422
observed in normal animals. This may be due to the heightened sympathetic tone and neural
423
remodeling that occurs in infarcted hearts,(2) which can be improved by interruption of
424
efferent and afferent fibers through the stellate ganglia and removal of these cardiac neurons.
425
It has been demonstrated both in this infarct model(26) and in patients with ischemic
426
and non-ischemic cardiomyopathy, that scar regions are rarely composed of homogeneous
427
and dense fibrotic tissue (which would not give rise to any electrical signal), and contain many
428
islands of live myocardium.(24, 26, 32, 49) These regions of live myocardium or channels
429
within “scar” give rise to fractionated bipolar electrograms, which have been shown to be
430
good targets of catheter ablation in patients with ventricular tachycardia.(19, 32, 40) However,
431
these same scar regions with intermingling myocytes have heterogenous innervation(9, 44)
432
that can lead to regions of delayed activation and conduction block, allowing for reentry and
433
ventricular arrhythmias to occur.(3, 34) In this study, we noted that in two animals, regions of
434
slow activation along the septal border zones of infarcts were improved after CSD, either at
435
baseline or during MCG stimulation, suggesting that CSD allowed for more uniform cardiac
436
activation, an anti-arrhythmic effect. More homogenous activation could be either due to
437
earlier activation of “late” areas, or more likely, due to slower activation of the surrounding
438
regions as a result of disruption of sympathetic efferent fibers.
439
MCG Stimulation After CSD
17
440
A theoretical concern with performing bilateral CSD in patients with cardiomyopathy
441
had been the possibility of eliminating sympathetic pathways that may be necessary for
442
day-to-day activities and exercise. In this study, efferent innervation from the MCG remained
443
intact after CSD, and CSD did not lead to any hemodynamic compromise in the porcine
444
model.
445
Stellate ganglia stimulation has been reported to increase DOR and Tp-Te
446
interval.(45, 50) Tp-Te interval represents both transmural and whole heart DOR and
447
increases risk of sudden cardiac death.(8, 27, 33) In this study, MCG stimulation also
448
increased DOR and Tp-Te interval in infarcted hearts. Importantly, CSD mitigated the effects
449
of MCG stimulation on DOR and Tp-Te interval in the setting of chronic myocardial infarction,
450
a novel finding of this study. The electrical stability that results from CSD in infarcted hearts
451
during sympathetic activation, and the lack of hemodynamic compromise is reassuring.
452
Limitations
453
Electrograms were recorded only from ventricular epicardium. Therefore, intramural
454
and endocardial effects were not assessed. This study was performed in a porcine model,
455
and given interspecies differences, direct interpolation to humans requires additional studies.
456
However, Isoflurane, which can suppress autonomic activity and was used for general
457
anesthesia during the surgical portion of the protocol. However, anesthesia was switched to
458
α-chloralose during the stimulation and CSD portions of the protocol. In addition, ARI and
459
Tp-Te interval were not corrected for increases in HR. Therefore, increases in Tp-Te interval
460
observed with stimulation are likely a conservative estimate of the actual effects. Given
461
different stimulation currents to achieve the same hemodynamic threshold, direct comparison
462
of parameters in MI vs. normal hearts was not performed. However, stimulation currents for
463
right and left stellate ganglia vs. MCG were similar. Finally, direct comparison of ARI values at
464
baseline or after CSD in infarcted compared to normal hearts cannot be made as normal
465
animals did not undergo a sham myocardial infarction procedure, did not have VT inducibility
18
466
testing, and had an additional BSG and MCG stimulation where the time course of effects of
467
BSG stimulation to MCG stimulation was compared. Finally, VT inducibility was not tested
468
during MCG stimulation. However, VT inducibility, by the nature of its ventricular pacing, does
469
cause sympathetic activation,(18, 35, 42) suggesting that the beneficial effects of CSD are
470
most influential during a state of elevated sympathetic tone.
471
472
Conclusions
473
Both MCG and stellate ganglia contribute significantly to cardiac sympathetic
474
innervation. In addition, VT inducibility in animals with chronic MI is significantly reduced by
475
bilateral CSD, even acutely. A mechanism for this benefit is the improvement in the increase
476
in DOR and Tp-Te interval prolongation observed with sympathetic activation. Furthermore,
477
efferent innervation via the MCG remains intact after bilateral CSD and hemodynamic
478
parameters remain stable.
479
480
481
482
19
483
FUNDING/GRANTS
484
This study was supported by NIH1DP2HL132356 and AHA 11FTF755004 to MV and NHLBI
485
R01HL084261 to KS.
486
20
487
DISCLOSURES
488
None for all authors.
489
490
21
491
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493
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667
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26
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670
FIGURE LEGENDS
671
672
Figure 1. Isolation of the middle cervical ganglia and Tp-Te interval and ARI recordings.
673
(A) Anatomy of MCG and surrounding tissue is shown. The MCG sits just at the thoracic inlet
674
and provides cardiopulmonary nerves that innervate the heart. (B) Customized bipolar needle
675
electrodes were placed in the isolated MCG. (C) The method for the measurement of Tp-Te
676
interval from surface ECG is shown. The peak of the T wave determined as the highest
677
voltage of the T wave, T-p. T-end (T-e) was determined by the tangent of the T wave. (D) The
678
region of scar in infarcted hearts predominantly involved the LVA apex, anterior, and
679
anterolateral walls. (E) 56-electrode sock is placed over the ventricles to obtain unipolar
680
electrograms that are used for ARI analysis. (F) The template for the polar maps used to
681
display regional ARIs from the sock electrodes is shown. MCG = middle cervical ganglion,
682
Ant = anterior, Lat = lateral, Post = posterior, RVOT = right ventricular outflow tract.
683
684
Figure 2. Experimental protocol in normal hearts and effect of bilateral stellate ganglia
685
compared to bilateral MCG stimulation (A) Timeline of the experimental protocol in 6
686
normal animals. (B) In all normal animals, bilateral MCG stimulation had a similar effect on
687
ARI compared to bilateral stellate ganglia stimulation (C) Polar maps from a normal animal
688
show the effects of MCG and stellate ganglia stimulation on ARI. Blue dashed lines indicate
689
course of left anterior descending coronary artery. Dashed circle indicates regions of scar on
690
polar maps. BL = baseline, BSGS = bilateral stellate ganglia stimulation, BMCGS = bilateral
691
middle cervical ganglia stimulation. *BMCGS or BSGS was performed in a random order,
692
LAD = left anterior descending coronary artery.
693
694
Figure 3. (A) The time course of ARI shortening with bilateral stellate ganglia stimulation was
695
similar to bilateral MCG stimulation (n = 6). (B) There were no significant regional differences
27
696
between bilateral stellate and bilateral MCG stimulation in normal hearts (P values > 0.05 for
697
all regions, n = 6). (c) Apical ventricular pacing pre-CSD demonstrated shorter global ARIs
698
than right atrial (RA) pacing in normal animals (n = 6) at the same cycle lengths. However,
699
after CSD, there was no significant difference in ARI between ventricular and atrial pacing,
700
suggesting that apical pacing may cause reflex sympathetic activation that is prevented by
701
CSD. Ant = anterior, Lat = lateral, Post = posterior wall, RV = right ventricle, LV =left ventricle,
702
RA = right atrium. BSGS = bilateral stellate ganglia stimulation. BMCGS = bilateral middle
703
cervical ganglia stimulation.
704
705
Figure 4. Effects of CSD in Normal Animals. (A) There was no difference in global ARI in
706
normal heart before compared to after CSD. (B) Bilateral MCG stimulation after CSD had
707
similar effects on global ARI compared to before CSD, with significant ARI shortening
708
observed. (C) There were no differences in the regional effects of MCG stimulation after CSD
709
compared to before CSD. (D) Before CSD, bilateral MCG stimulation increased dispersion of
710
repolarization in normal hearts, and this effect was not modified by CSD. (E) Bilateral MCG
711
stimulation in normal hearts also increased Tp-Te interval, with no differences observed in
712
this parameter before compared to after CSD in normal hearts.
713
714
Figure 5. Effects of Hexamethonium on MCG stimulation. (A) The increase in global ARI
715
during right vagal nerve stimulation was no longer observed after the infusion of
716
hexamethonium in normal animals (n = 6). (B) Global ARI during bilateral MCG stimulation
717
significantly decreased even after administration of hexamethonium in all normal hearts (n =
718
6). (C) Percent change in global ARI during right vagal nerve stimulation and bilateral MCGS
719
stimulation showed that hexamethonium significantly blocked nicotinic receptors, but did not
720
affect the response to bilateral MCG stimulation. Hex = hexamethonium, VNS = vagal nerve
721
stimulation.
28
722
723
Figure 6. Experimental protocol in infarcted hearts and effect of bilateral stellate
724
ganglia compared to bilateral MCG stimulation (A) Timeline the experimental protocol in
725
12 infarcted animals. (B) In all infarcted animals, bilateral stellate ganglia stimulation
726
significantly decreased ARI as did bilateral MCG stimulation. Bilateral MCG stimulation,
727
however, caused greater ARI shortening than bilateral stellate stimulation (C) Polar maps
728
from an infarcted animal show the effects of MCG and stellate ganglia stimulation on ARI.
729
Black dashed lines indicate region of the infarct on the polar maps. Blue dashed lines indicate
730
course of left anterior descending coronary artery. Dashed circle indicates regions of scar on
731
polar maps. BL = baseline, BSGS = bilateral stellate ganglia stimulation, BMCGS = bilateral
732
middle cervical ganglia stimulation. *BMCGS or BSGS was performed in a random order,
733
LAD = left anterior descending coronary artery.
734
735
Figure 7. Effects of CSD and VT inducibility pre and post CSD (A) Epicardial global ARI
736
from infarcted animals significantly increased with CSD (n = 12). (B) Inducibility of VT/VF was
737
reduced after CSD in infarcted animals (n = 18, 12 were inducible at baseline. Of this 12, only
738
6 were inducible after CSD). (C) An example of VT induction with ventricular extra-stimulus
739
pacing is shown. VT/VF was induced before CSD with double extra-stimuli at cycle lengths of
740
600/320/200 ms. After CSD, ERP was reached at an interval of 600/340 ms with double
741
extra-stimuli. Therefore, the S2 stimulus was increased by 20 ms to 600/360 ms (to allow for
742
consistent capture) and S3 was added and the interval reduced by 10 ms. The animal
743
reached ERP at 270 ms with triple extra-stimuli (S3). Therefore, the S3 coupling interval was
744
increased to 290 ms (to allow for consistent capture), and S4 was reduced by 10 ms, starting
745
at 600/360/290/400 ms. Despite reducing S4 extra-stimulus (triple extra-stimulus testing) to a
746
coupling interval of 200 ms, no ventricular arrhythmias could be induced. Black dashed lines
747
indicate region of the infarct on the polar maps.
29
748
749
Figure 8. MCG stimulation and its effects before and after CSD on infarcted hearts. (A)
750
Global ARI at baseline and during bilateral MCG Stimulation after CSD and percentage
751
change in ARI pre- vs. post-CSD during BMCGS in infarcted hearts (n = 12). MCG stimulation
752
decreased ARI despite CSD. (B) Examples of polar maps at baseline and during MCG
753
stimulation after CSD in infarcted hearts. Dashed-black lines indicates course of LAD.
754
Dashed blue circles indicates region of scar. (C) Although MCG stimulation significantly
755
increased DOR before CSD, this effect was mitigated after CSD in infarcted hearts (n = 12).
756
(D) The prolongation in Tp-Te interval during MCG stimulation was reduced by CSD in
757
infarcted hearts. BL = baseline, BMCGS = bilateral MCG stimulation, LAD = left anterior
758
descending coronary artery.
759
760
Figure 9. Modulation of propagation and activation time by CSD. (A) Polar maps of
761
activation time/sequence obtained during scar/apical pacing in this infarct animal
762
demonstrated a localized region at the septal border zone of the infarct that was activated
763
late as compared to it surrounding area. This area of functional block (localized regions of
764
late activation, delineated as “II”) pre-CSD was no longer observed after CSD, and the entire
765
area was activated more homogenously. (B) Polar maps of activation time/sequence during
766
scar pacing at baseline and during bilateral MCG stimulation before and after CSD in a
767
different infarcted animal are shown.
768
activation are seen at the border zone of the infarct, creating a potential isthmus or area of
769
slow conduction that could serve as the substrate for a reentrant circuits. Both of these
770
regions of late myocardial activation are no longer observed during MCG stimulation after
771
CSD. After CSD, the entire region is more uniformly activated.
772
bilateral middle cervical ganglia stimulation. Black dashed lines indicate region of the infarct
773
on the polar maps.
During MCG stimulation, two localized regions of late
BL = baseline, BMCGS =
30
774
775
Figure 10. Efferent and afferent cardiac sympathetic pathways. Afferent fibers from the
776
myocardium that traverse through the MCG pass through the stellate ganglia before reaching
777
the spinal cord, and some of these pathway are interrupted by CSD. In addition,
778
pre-ganglionic efferent fibers that pass from the spinal cord through the stellate ganglia and to
779
the MCG and any post-ganglionic fibers that arise from the stellate ganglia and innervate the
780
myocardium are also interrupted. However, efferent post-ganglionic fibers from MCG neurons
781
to the myocardium remain intact despite CSD. Aff = afferent neurons, Eff = efferent neurons,
782
DRG = dorsal root ganglion, IML = intermediolateral nucleus, DH = dorsal horn of the spinal
783
cord.
784
31
Figure
Figure
1. 1
B
A
B
Subclavian Artery
MCG
Sympathetic Chain
Ansa Subclavia
C
Needle Electrode
Cardiopulmonary
Nerves
MCG
F
E
D
RV Ant
RV Lat
RVOT
Infarcted
Areas
LAD
RV
LV Ant
LAD
LV
Infarcted
Area
Infarcted
Area
LV Lat
RV Post
Apex
LV Post
Figure 1. Isolation of the middle cervical ganglia 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) The method
for the measurement of Tp-Te interval from surface ECG is shown. The peak of the T
wave 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 LVA 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)
The template for the polar maps used to display regional ARIs from the sock electrodes
is shown. MCG = middle cervical ganglion, Ant = anterior, Lat = lateral, Post = posterior,
RVOT = right ventricular outflow tract.
Figure 2.
A. Timeline of Experimental Protocol in Normal Animals
HEX
CSD
30min
30min
Isola7onof BMCGS
MCGand orBSGS*
Stellate (30sec)
Ganglia
30min
30min
BSGS
BMCGS
orBSGS* orBMCGS*
(60sec)
(30sec)
BMCGS
orBSGS*
(60sec)
B
400
350
300
350
300
P < 0.05
14
Change in ARI (%)
P < 0.05
BL
1
BSGS
2
200
BL
1 BMCGS
2
VNS
(20sec)
RV
LV
10
Apex
BL
8
6
LAD
RV
2
200
10min
LAD
12
4
250
250
P = 0.4
30min
BMCGS
(30sec)
C
Global ARI (ms)
Global ARI (ms)
400
30min
0
LV
BSGS
1 BMCGS
2
Apex
ARI (ms)
376
364
352
340
327
315
303
291
279
266
254
242
BSGS
VNS BMCGS
(20sec) (30sec)
LAD
RV
LV
Apex
BL
LAD
RV
LV
Apex
BMCGS
Figure 2. Experimental protocol in normal hearts and effect of bilateral stellate
ganglia compared to bilateral MCG stimulation (A) Timeline of the experimental
protocol in 6 normal animals. (B) In all normal animals, bilateral MCG stimulation had a
similar effect on ARI compared to bilateral stellate ganglia stimulation (C) Polar maps
from a normal animal show the effects of MCG and stellate ganglia stimulation on ARI.
Blue dashed lines indicate course of left anterior descending coronary artery. Dashed
circle indicates regions of scar on polar maps. BL = baseline, BSGS = bilateral stellate
ganglia stimulation, BMCGS = bilateral middle cervical ganglia stimulation. *BMCGS or
BSGS was performed in a random order, LAD = left anterior descending coronary artery.
Figure 3.
Percent Change in ARI (%)
BSGS
A
BMCGS Pre-CSD
0
-5
-10
-15
-20
-25
5sec
10sec
15sec
20sec
30sec
45sec
60sec
B
Change in ARI (%)
30
BSGS
25
BMCGS Pre-CSD
20
15
10
5
0
Apex
Ant
Lat
Post
Post
Lat
LV
Ant
RVOT
RV
RA Pacing
C
Global ARI (ms)
260
P < 0.05
Apical Pacing
P = 0.6
250
240
P = 0.5
P < 0.05
230
220
210
200
BL Pre-CSD
BMCGS Pre-CSD
Pre-CSD
BL Post-CSD
BMCGS Post-CSD
Post-CSD
Figure 3. (A) The time course of ARI shortening with bilateral stellate ganglia stimulation
was similar to bilateral MCG stimulation (n = 6). (B) There were no significant regional
differences between bilateral stellate and bilateral MCG stimulation in normal hearts (P
values > 0.05 for all regions, n = 6). (c) Apical ventricular pacing pre-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 = right atrium. BSGS = bilateral stellate
ganglia stimulation. BMCGS = bilateral middle cervical ganglia stimulation.
Figure 4.
A
B
300
250
200
Pre1
CSD
Post2
CSD
ARI (ms)
Pre-CSD
BMCGS
Percent Change in ARI (%)
Global ARI (ms)
350
400
Global ARI (ms)
P = 0.2
400
Post-CSD
355
349
342
336
329
323
316
310
303
297
291
284
P < 0.03
350
300
250
200
BL
1
25
20
P = 0.6
15
10
5
0
1
PreCSD
BMCGS
2
Post-CSD
2
PostCSD
BL
BMCGS Post-CSD
350
*
†
*
300
*
*
*
*
*
250
200
Apex
Ant
Lat
Post
Post
Lat
LV
Ant RVOT
0
Apex
Ant
Lat
Post
Post
Lat
Ant
RVOT
RV
LV
700
700
600
600
400
300
80
P<0.05
Tp-Te Interval (ms)
800
P<0.05
500
Normal Hearts
Post-CSD - Normal Hearts
DOR (ms2)
DOR (ms2)
10
E
Pre-CSD - Normal Hearts
200
BMCGS Post-CSD
20
RV
D
800
BMCGS Pre-CSD
30
500
400
P=0.1
P=0.1
60
40
20
300
1
BL
2
BMCGS
200
BL
1
BMCGS
2
Percent Change in Tp-Te (%)
ARI (ms)
400
Percent change in ARI (%)
C
P=0.9
80
60
40
20
0
0
BL
BMCGS
Pre-CSD
BL
BMCGS
Post-CSD
PreCSD
PostCSD
Figure 4. Effects of CSD in normal animals. (A) There was no difference in global ARI
in normal heart before compared to after CSD. (B) Bilateral MCG stimulation after CSD
had similar effects on global ARI compared to before CSD, with significant ARI
shortening observed. (C) There were no differences in the regional effects of MCG
stimulation after CSD compared to before CSD. (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 TpTe interval, with no differences observed in this parameter before compared to after CSD
in normal hearts.
Figure 5.
A
B
Right VNS
MCG Stimulation
P < 0.05
350
300
250
400
P = 0.6
P < 0.05
Global ARI (ms)
Global ARI (ms)
400
350
300
250
BLS%m
Pre-Hex BLS%m
Post-Hex
Pre-HexPostHex
C
P < 0.05
BLS%m
Pre-Hex BLS%m
Post-Hex
Pre-HexPostHex
Percent Change in ARI (%)
P = 0.3
12
10
8
P < 0.05
6
4
2
0
BLS%m
RVNS
RightVNS
BLS%m
BMCGS
MCGS%mula%on
Figure 5. Effects of hexamethonium on MCG stimulation. (A) The increase in global
ARI during right vagal nerve stimulation was no longer observed after the infusion of
hexamethonium 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) Percent change in global ARI during right vagal nerve
stimulation and bilateral MCGS stimulation showed that hexamethonium significantly
blocked nicotinic receptors, but did not affect the response to bilateral MCG stimulation.
Hex = hexamethonium, VNS = vagal nerve stimulation.
Figure 6.
A Timeline of Creation of Myocardial Infarct and Mapping Experiments in Infarcted Animals
CSD
4-6weeks
30min
30min
30min
Voltage
VT/VF BMCGS BMCGS
Mapping Induc+on orBSGS orBSGS*
Myocardial
Infarc+on
C
B
350
300
400
424
402
379
357
334
312
289
267
244
222
200
177
BL
15
300
LAD
10
250
5
200
200
0
2
BSGS
LAD
Apex
20
250
1
BL
VT/VF BMCGS
Induc+on
RV
25
350
30min
LV
Change in ARI (%)
Global ARI (ms)
400
P = 0.02
P < 0.01
P < 0.01
Global ARI (ms)
30min
BL
1
BMCGS
2
RV
LV
BSGS
1
BMCGS
2
Apex
LAD
RV
LV
Apex
BL
LAD
RV
LV
ARI (ms)
BSGS
Apex
BMCGS
Figure 6. Experimental protocol in infarcted hearts and effect of bilateral stellate
ganglia compared to bilateral MCG stimulation (A) Timeline the experimental
protocol in 12 infarcted animals. (B) In all infarcted animals, bilateral stellate ganglia
stimulation significantly decreased ARI as did bilateral MCG stimulation. Bilateral MCG
stimulation, however, caused greater ARI shortening than bilateral stellate stimulation
(C) Polar maps from an infarcted animal show the effects of MCG and stellate ganglia
stimulation on ARI. Black dashed lines indicate region of the infarct on the polar maps.
Blue dashed lines indicate course of left anterior descending coronary artery. Dashed
circle indicates regions of scar on polar maps. BL = baseline, BSGS = bilateral stellate
ganglia stimulation, BMCGS = bilateral middle cervical ganglia stimulation. *BMCGS or
BSGS was performed in a random order, LAD = left anterior descending coronary artery.
Figure 7.
A
LAD
Global ARI (ms)
400
350
300
250
Pre1
CSD
Post2
CSD
444
432
421
409
397
385
374
362
350
339
327
315
ARI (ms)
P < 0.05
RV
LV
Pre-CSD
LAD
RV
VT/VF Inducibility (%)
P < 0.05
0.05
B
60
40
20
0
LV
pre-CSD
post-CSD
Pre-CSD
Post-CSD
Post-CSD
C
Post-CSD
Pre-CSD
500ms
500ms
III
II
V1
V1
V3
V3
RVD
RVD
RVP
RVP
Figure 7. Effects of CSD and VT Inducibility pre and post CSD (A) Epicardial global
ARI from infarcted animals significantly increased with CSD (n = 12). (B) Inducibility of
VT/VF was reduced after CSD in infarcted animals (n = 18, 12 were inducible at
baseline. Of this 12, only 6 were inducible after CSD). (C) An example of VT induction
with ventricular extra-stimulus pacing is shown. VT/VF was induced before CSD with
double extra-stimuli at cycle lengths of 600/320/200 ms. After CSD, ERP was reached at
an interval of 600/340 ms with double extra-stimuli. 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 reducing S4 extra-stimulus (triple extra-stimulus testing) to a coupling interval of
200 ms, no ventricular arrhythmias could be induced. Black dashed lines indicate region
of the infarct on the polar maps.
Figure8.
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
BL
1
BMCGS
2
25
20
15
10
5
0
1
PreCSD
2
PostCSD
ARI (ms)
C
LAD
LAD
RV
RV
LV
LV
Apex
Apex
Post-CSD
BMCGS Post-CSD
D
1200
1000
1000
DOR (ms2)
1200
800
600
400
200
80
1400
P=0.03
2
BMCGS
800
600
200
P=0.02
P=0.4
400
1
BL
P=0.01
BL
1
BMCGS
2
60
40
20
Percent Change in Tp-Te (%)
1400
Infarcted Hearts
Post-CSD – Infarcted Hearts
Tp-Te Interval (ms)
Pre-CSD- Infarcted Hearts
DOR (ms2)
371
353
334
316
298
279
261
243
224
206
187
169
P<0.05
80
60
40
20
0
0
BL
BMCGS
Pre-CSD
BL
BMCGS
Post-CSD
PreCSD
PostCSD
Figure 8. MCG stimulation and its effects before and after CSD on infarcted hearts.
(A) Global ARI at baseline and during bilateral MCG Stimulation after CSD and
percentage change in ARI pre- vs. post-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. Dashed-black lines indicates
course of LAD. Dashed blue circles 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. BL = baseline, BMCGS = bilateral
MCG stimulation, LAD = left anterior descending coronary artery.
Figure 9.
A
AT (ms)
78
72
66
61
55
49
43
37
32
26
20
14
Pre-CSD
Post-CSD
B
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
Figure 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 to it surrounding area. This area of functional block (localized
regions of late activation, delineated as “II”) pre-CSD was no longer observed after CSD,
and the entire area was activated more homogenously. (B) Polar maps of activation
time/sequence during scar pacing at baseline and during bilateral MCG stimulation
before and after CSD in a different infarcted animal are shown. During MCG stimulation,
two 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. BL = baseline, BMCGS = bilateral middle cervical ganglia
stimulation. Blackdashedlinesindicateregionoftheinfarctonthepolarmaps.
Figure 9
Figure 10.
Brainstem
MCG
Stellate
DRG
Eff
DH
Eff
Aff
IML
Aff
DH
IML
HEART
DH
IML
CSD
Pre-ganglionic efferent sympathetic fibers
Post-ganglionic efferent sympathetic fibers
Afferent sympathetic fibers
Intraganglionic Information Processing
Sympathetic
Chain
Spinal Cord
Figure 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 pathway are interrupted by CSD. In
addition, pre-ganglionic efferent fibers that pass from the spinal cord through the stellate
ganglia and to the MCG and any post-ganglionic 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.
Table 1
Normal
Animals
(N = 6)
BL
(Pre-BSGS)
BL
BMCGS
BSGS
(PreMCGS)
(Pre-CSD)
BL
BMCGS
Pre-CSD
Post-CSD
(Pre-MCGS
Post-CSD)
(Post-CSD)
HR (bpm)
84±17
98±13*
89±14
103±10*
86±12
89±8
90±12
104±10*
Max dP/dt
1178±166
2391±724*
1086±116
2364±531*
1032±157
1087±296
1007±228
2232±467*
Min dP/dt
-1126±317
-1149±462
-1172±337
-1174±302
-1121±353
-1094±286
-984±266
-1149±382
LVESP
103±20
147±23*
99.5±21
134±24*§
97.5±22
94±16
87±13
125±20*¥
Mean±SD reported. HR = heart rate, LVESP = left ventricular end-systolic pressure, BSGS = bilateral stellate ganglia
stimulation, BMCGS = bilateral middle cervical ganglia stimulation. Values represent percent change in parameters from
pre-stimulation value. *P value < 0.05 for percentage change from baseline (pre-stimulation).¥ P= 0.08 for percentage
increase in LVESP with BMCGS pre vs. post CSD. § P = 0.02 for comparison of % change in LVESP for BSGS vs.
BMCGS. Pre-CSD represents hemodynamic values immediately before removal of the stellate ganglia. Post-CSD values
represent hemodynamic parameters after a 30 minute period of stabilization after removal of stellate ganglia
Table 2
Baseline
(ng/ml)
BSGS
(ng/ml)
Normal pigs (CS)
0.38±0.09
8.70±2.28
Normal pigs (IVC)
0.58±0.22
Infarct pigs (CS)
1.35±0.41
*
1.52±0.29 *
7.47±1.48 *
Infarct pigs (IVC)
1.97±0.54
2.53±0.28
Baseline
(ng/ml)
BMCGS
(ng/ml)
0.54±0.16
13.73±4.47
1.79±0.51
*
1.61±0.29 *
7.83±2.16 *
1.89±0.46
3.78±0.95
0.55±0.07
CS = coronary sinus, IVC = inferior vena cava, BSGS = bilateral stellate ganglia stimulation, BMCGS =
bilateral middle cervical ganglia stimulation, *P<0.05 compared to baseline.
*
Table 3
Infarcted
Animals
(N = 12)
BL
(Pre-BSGS)
BL
BMCGS
BSGS
(PreBMCGS)
(Pre-CSD)
BL
BMCGS
Pre-CSD
Post-CSD
(Pre-MCGS
Post CSD)
(Post-CSD)
HR
85±10.7
94±21*
84±11.8
112±22*§
83±13
84±13
84±13
114±24*
Max dP/dt
1246±390
2127±315*
1123±332
2271±9678*¥
984±349
880±337
878±338
1797±937*
Min dP/dt
-1280±582
-1157±542
-1179±537
-1093±635
-1090±571
-1025±634
-1027±630
-958±574
LVESP
90±20
123±28
86±21
99±21§
78±25
69±22¶
69±22
86±26
Mean±SD reported. HR = heart rate, LVESP = left ventricular end-systolic pressure, BSGS = bilateral stellate ganglia
stimulation, BMCGS = bilateral middle cervical ganglia stimulation. Values represent percent change in parameters from
pre-stimulation value. *P value < 0.05 for percentage change from baseline (pre-stimulation).¥ P= 0.06 for percentage
increase in dP/dt max with BMCGS compared to BSGS. §P < 0.01 for comparison of BMCGS vs. BSGS. ¶ P=0.02 for
comparison of pre-CSD vs. post CSD. Pre-CSD represents hemodynamic values immediately before removal of the
stellate ganglia. Post-CSD values represent hemodynamic parameters after a 30 minute period of stabilization after
removal of stellate ganglia