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Am J Physiol Regul Integr Comp Physiol 301: R775–R782, 2011.
First published June 15, 2011; doi:10.1152/ajpregu.00140.2011.
Cardiac spinal deafferentation reduces the susceptibility to sustained
ventricular tachycardia in conscious rats
Heidi L. Lujan, Sandhya Krishnan, and Stephen E. DiCarlo
Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan
Submitted 16 March 2011; accepted in final form 10 June 2011
cardiovascular risks; ischemia; dorsal root ganglia
(SCD) causes more than 350,000 deaths
annually in the United States (1, 76, 78) and is most commonly
caused by ventricular tachyarrhythmias that culminate in ventricular fibrillation (VF) (6, 28). The most common cause of
SCD is acute myocardial ischemia. Multiple ischemic metabolites, including ATP, thromboxane A2, serotonin (5-hydroxytryptamine), histamine, lactic acid (protons), reactive oxygen
species, and bradykinin are released during myocardial ischemia and reperfusion and stimulate cardiac spinal afferents (5,
24 –27, 45, 53, 70, 71) leading to angina pectoris and excitatory
cardiac-cardiovascular reflex responses (35, 45, 49). The excitatory cardiac-cardiovascular reflex plays a major role in the
genesis of ventricular arrhythmias (59). Disruption of this
excitatory sympathetic reflex has been used successfully to
reduce arrhythmias in high-risk patients with structural heart
disease (8), following myocardial infarction (67), patients with
long QT syndrome (19, 62), and patients with catecholamin-
SUDDEN CARDIAC DEATH
Address for reprint requests and other correspondence: S. E. DiCarlo,
Wayne State Univ. School of Medicine, 540 E. Canfield Ave., Detroit, MI
48201 (e-mail: [email protected]).
http://www.ajpregu.org
ergic polymorphic ventricular tachycardia (19, 75), as well as
in animal models during coronary artery occlusion (58, 59, 63,
65). Importantly, all of these previous studies, with the exception of Schwartz et al. (59), have disrupted both the afferent
and efferent limbs or only the efferent limb of the excitatory
sympathetic reflex (43). In contrast, Schwartz et al. (59) documented that disruption of the afferent limb, in anesthetized
and vagotomized dogs and cats, decreased the absolute number
of ectopic beats elicited by brief occlusion and reperfusion of
the circumflex and/or the anterior descending coronary artery.
However, surrogate endpoints for VF, such as the absolute
number of ectopic beats, may be misleading (2) and not
representative of VF or SCD (69). Thus, to date, the effects of
disruption of the afferent limb on the response to coronary
occlusion-induced VF have not been studied.
Based on these clinical and experimental results, we tested
the hypothesis that cardiac spinal deafferentation reduces the
susceptibility to sustained ventricular tachycardia initiated by
occlusion of the left main coronary artery. Conscious, chronically instrumented rats were studied to negate the confounding
effects of anesthetic agents and surgical trauma.
MATERIALS AND METHODS
Surgical Procedures
Experimental preparations and protocols were reviewed and approved by the Animal Care and Use Committee of Wayne State
University, Detroit, MI. The studies conformed to the American
Physiological Society guidelines and principles for research involving
animals. Two groups of adult male Sprague-Dawley rats were studied:
1) deafferentation (n ⫽ 6, bilateral excision of the T1-T5 dorsal root
ganglia) and 2) control (sham deafferentation; n ⫽ 6). All surgical
procedures were performed using aseptic surgical techniques. Rats
were anesthetized with pentobarbital sodium (50 mg/kg ip), atropinized (0.05 mg/kg ip), intubated, and prepared for aseptic surgery.
Supplemental doses of pentobarbital sodium (10 –20 mg/kg ip) were
administered if the rat regained the blink reflex or responded during
the surgical procedures.
Radiotelemetry implantation. After anesthesia was induced, a telemetry device [PhysioTel C50-PXT (Data Sciences International)
pressure, temperature, and electrocardiogram] was implanted in all
rats as previously described (17, 55), and a catheter was placed in the
intraperitoneal space for the infusion of fluids and drugs. Specifically,
the transmitter body, which contains the thermistor, and the intraperitoneal catheter were placed in the intraperitoneal space through a
ventral abdominal approach. The intraperitoneal catheter was exteriorized on the dorsal aspect of the neck. The pressure sensor of the
telemetry device, located within the tip of a catheter, was inserted into
the descending aorta for continuous, nontethered, recording of pulsatile arterial blood pressure. The electrical leads from the telemetry
device were placed in a modified lead II configuration by placing the
negative electrode slightly to the right of the manubrium and the
positive electrode at the anterior axillary line along the 5th intercostal
space. A minimum of 1 wk was allowed for recovery and for the
0363-6119/11 Copyright © 2011 the American Physiological Society
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Lujan HL, Krishnan S, DiCarlo SE. Cardiac spinal deafferentation
reduces the susceptibility to sustained ventricular tachycardia in conscious rats. Am J Physiol Regul Integr Comp Physiol 301: R775–R782,
2011. First published June 15, 2011; doi:10.1152/ajpregu.00140.2011.—
The response to myocardial ischemia is complex and involves the
cardio-cardiac sympathetic reflex. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an
excitatory sympathetic reflex, which plays a major role in the genesis
of ventricular arrhythmias. For example, brief myocardial ischemia
leads to ATP release, which activates cardiac spinal afferents through
stimulation of P2 receptors. Clinical work with patients and preclinical work with animals document that disruption of this reflex protects
against ischemia-induced ventricular arrhythmias. However, the role
of afferent signals in the initiation of sustained ventricular tachycardia
has not been investigated. Therefore, we tested the hypothesis that
cardiac spinal deafferentation reduces the susceptibility to sustained
ventricular tachycardia in adult (12–15 wk of age), conscious, male
Sprague-Dawley rats. To test this hypothesis, the susceptibility to
ventricular tachyarrhythmias produced by occlusion of the left main
coronary artery was determined in two groups of conscious rats:
1) deafferentation (bilateral excision of the T1-T5 dorsal root ganglia)
and 2) control (sham deafferentation). The ventricular arrhythmia
threshold (VAT) was defined as the time from coronary occlusion to
sustained ventricular tachycardia resulting in a reduction in arterial
pressure. Results document a significantly higher VAT in the deafferentation group (7.0 ⫾ 0.7 min) relative to control (4.3 ⫾ 0.3 min)
rats. The decreased susceptibility to tachyarrhythmias with deafferentation was associated with a reduced cardiac metabolic demand (lower
rate-pressure product and ST segment elevation) during ischemia.
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CARDIAC SPINAL REFLEX AND ARRHYTHMIAS
rats; however, the dorsal root ganglia were not cut. Cell bodies of
afferent fibers from the heart are located in the dorsal root ganglia of
spinal segments T1-T5 (59). Therefore, excision of dorsal root ganglia
from T1-T5 eliminated the main cardiac spinal (sympathetic) afferents
from the heart to the central nervous system. Ventral roots, which
contain the sympathetic efferent outflow, remained intact (59). All rats
were allowed to recover for 2 wk. Upon completion of the studies, the
site of the spinal deafferentation was confirmed by autopsy.
Experimental Procedures
Ventricular arrhythmia threshold. Conscious, unrestrained rats
were studied in their home cages for all experiments. Rats were
allowed to adapt to the laboratory environment for ⬃1 h to ensure
stable hemodynamic conditions. After the stabilization period, beat by
beat, steady-state preocclusion hemodynamic variables were recorded
over 10 to 15 s. Subsequently, the left main coronary artery was
temporarily occluded by use of the prolene suture. Specifically, acute
coronary artery occlusion was performed by pulling up on the suture
that was around the left main coronary artery (37). In control rats,
rapid changes in the ECG (peaked T wave followed by ST segment
elevation) as well as an increase in arterial pressure and heart rate
occur within seconds of pulling on the suture, documenting coronary
artery occlusion (36 –38, 40 – 43). In contrast, arterial pressure and
heart rate decrease during coronary artery occlusion in rats with
Fig. 1. Analog recordings (1 s) of arterial pressure (AP) and the ECG immediately before occlusion of the left main coronary artery (rest) and during the first
3 min of occlusion in 1 control rat and 1 rat that had the T1-T5 dorsal root ganglia bilaterally excised (Afferent-X). In control rats, rapid changes in the ECG
(peaked T wave followed by ST segment elevation) as well as an increase in AP and heart rate occur within seconds of pulling on the suture, documenting
coronary artery occlusion. In contrast, AP decreased during coronary artery occlusion in rats with Afferent-X, and there is a markedly lower elevation in the ST
segment (scale bar ⫽ 1 s).
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animals to regain their presurgical weight. During the recovery period,
the rats were handled, weighed, and acclimatized to the laboratory and
investigators.
Thoracotomy procedures. After the recovery period, the animals
were anesthetized as described above, and the hearts were approached
via a left thoracotomy through the 4th intercostal space. A coronary
artery occluder was made from an atraumatic needle holding 5.0gauge prolene suture (Ethicon). The needle and suture were passed
around the left main coronary artery 2–3 mm from the origin by
inserting the needle into the left ventricular wall under the overhanging left atrial appendage and bringing it out high on the
pulmonary conus. The needle was cut from the suture, and the two
ends of the suture were passed through a PE-50 polyethylene guide
tubing. The guide tubing with the two ends of the suture were then
exteriorized and secured at the back of the neck. The tubing was filled
with a mixture of Vaseline and mineral oil to prevent a pneumothorax.
At least 1 wk was allowed for recovery. During the recovery period,
the rats were handled, weighed, and acclimatized to the laboratory and
investigators.
Spinal deafferentation. After anesthesia was induced, rats were
intubated and positioned prone over a thoracic roll that slightly flexed
the trunk. The T1-T4 thoracic vertebrae were exposed via a midline
dorsal incision, and the spinous processes and laminae were removed.
Subsequently, the T1-T5 dorsal root ganglia were carefully isolated
and excised bilaterally. Identical procedures were used for the control
CARDIAC SPINAL REFLEX AND ARRHYTHMIAS
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RESULTS
Fig. 2. Recordings of AP immediately before occlusion of the left main
coronary artery, at the onset of coronary artery occlusion (dotted line), and
during 4 min of the ischemic period for 1 control rat and 1 rat that had the
T1-T5 dorsal root ganglia bilaterally excised (Afferent-X). In control rats, an
increase in AP occurs within seconds of occluding the left main coronary
artery and remained elevated for the duration of the occlusion. In contrast, AP
decreased during coronary artery occlusion in rats with Afferent-X. In this
example, the control rat experienced ventricular tachycardia before 4 min as
documented by the sudden reduction in AP.
cardiac (sympathetic) spinal deafferentation, and there is a markedly
lower elevation in the ST segment (Figs. 1 and 2). The reduction in
arterial pressure is likely the result of the reduced cardiac output that
occurs during coronary artery occlusion (39, 42); and the reduced
heart rate and lower elevation in the ST segment are likely the result
of disruption of the excitatory cardiac-cardiovascular reflex responses
(35, 45, 49). The coronary artery occlusion was maintained until the
onset of sustained ventricular tachycardia but no longer than 10 min
to prevent permanent myocardial damage (52). The ventricular arrhythmia threshold (VAT) was defined as the time from coronary
artery occlusion to sustained ventricular tachycardia resulting in a
reduction in arterial pressure. If the time to sustained ventricular
tachycardia exceeded 10 min, the occlusion was stopped and 10 min
was used as the VAT. Ventricular tachycardia was defined as sustained ventricular rate (absence of P wave, wide bizarre QRS complex) ⬎ 1,000 beats/min, with a reduction in arterial pressure to ⬃40
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Figure 3 presents the VAT in the two groups of rats (control
and deafferentation). The VAT was significantly longer in the
deafferentation group compared with the control group (7.0 ⫾
0.7 vs. 4.3 ⫾ 0.3 min, respectively). Importantly, in the
deafferentation group, the VAT exceeded the 10-min occlusion
limit in one animal; thus 10 min was used as the VAT. This
animal experienced sustained ventricular tachycardia upon
reperfusion. No animals in the control group exceeded the
10-min occlusion limit.
Mean arterial blood pressure, heart rate, ST segment elevation, and rate-pressure product immediately before the occlusion (rest) and during the first 3 min of occlusion in the two
Fig. 3. Ventricular arrhythmia threshold (VAT) in control rats and rats that had
their T1-T5 dorsal root ganglia bilaterally excised (Afferent-X). The VAT was
significantly longer in the Afferent-X group compared with the control group
(7.0 ⫾ 0.7 vs. 4.3 ⫾ 0.3 min, respectively). *P ⬍ 0.05, control vs. Afferent-X.
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mmHg. Normal sinus rhythm appeared upon termination of the
occlusion by gently compressing the thorax. Without compressing the
thorax, the sustained ventricular tachycardia progresses to VF. VF
was defined as a ventricular rhythm without recognizable QRS complex in which signal morphology changed from cycle to cycle and for
which it was impossible to estimate heart rate. In the event that the
animal did not resume normal sinus rhythm, cardioversion was
achieved (after the rat lost consciousness) with the use of one shock
(10 J) of DC current.
Data analysis. All recordings were sampled at 2 kHz and the data
were expressed as means ⫾ SE. All data were the average of every
beat during the last 10 –15 s of the period.
A Student’s unpaired t-test was used to compare the VAT (Fig. 3)
between the deafferentation and control groups. In addition, a twofactor ANOVA with repeated measures on one factor, was used to
compare mean arterial blood pressure, heart rate, ST segment elevation,
and rate-pressure product immediately before the occlusion (rest) and
during the first 3 min of occlusion between the two groups (Fig. 4). The
first 3 min of occlusion were chosen (as the standardized time points)
to compare identical time points between groups. This was necessary
because the VAT was different between the deafferenation and control groups. Importantly, no animal in either group experienced
sustained ventricular tachycardia before 3 min of occlusion.
Finally, a Student’s unpaired t-test was used to compare mean
arterial blood pressure, heart rate, ST segment elevation, and ratepressure product immediately before the onset of ventricular tachycardia between the deafferenation and control groups (Fig. 5).
The ECGs were analyzed off-line to measure the ST segment
elevation (voltage difference between the baseline and J point) using
the ECG analysis software for Chart [ADInstruments (68)]. The
rate-pressure product, an index of myocardial oxygen demand, was
calculated as systolic blood pressure ⫻ heart rate/1,000 (30).
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CARDIAC SPINAL REFLEX AND ARRHYTHMIAS
groups are presented in Fig. 4. The first 3 min of occlusion
were chosen (as the standardized time points) to compare
identical time points between groups. This was necessary
because the VAT was different between the two groups. All
values were significantly lower in the deafferentation group
(significant group effect).
Mean arterial blood pressure, heart rate, ST segment elevation, and rate-pressure product immediately before the onset of
sustained ventricular tachycardia in the control and deafferenation groups are presented in Fig. 5. Mean arterial pressure and
ST segment elevation were not different between the two
groups. In contrast, heart rate and double product were significantly lower in the deafferenation group.
DISCUSSION
In this study, we tested the hypothesis that cardiac spinal
deafferentation reduces the susceptibility to sustained ventricular tachycardia, initiated by occlusion of the left main coronary artery. To test this hypothesis, we recorded the VAT
induced by myocardial ischemia in control and deafferented
conscious rats. Results document a significantly higher VAT in
the deafferented group (Fig. 3). The reduced susceptibility to
ventricular tachyarrhythmias was associated with a reduced
cardiac metabolic demand during ischemia (lower mean arterial pressure, heart rate, rate-pressure product, and ST segment
AJP-Regul Integr Comp Physiol • VOL
elevation, Fig. 4). The higher VAT in the deafferented group
extends previous reports that disruption of the excitatory cardio-cardiac sympathetic reflex is protective against ventricular
arrhythmias (19, 58, 59, 62, 63, 65, 67, 75).
The present study also extends the pioneering work of
Schwartz et al. (59), which documented that C8-T5 dorsal root
section in anesthetized and vagotomized dogs and cats decreased the absolute number of ectopic beats elicited by multiple brief (5–90 s) occlusions and reperfusions (60 s) of the
circumflex and/or the anterior descending coronary artery. The
authors concluded that dorsal root section reduced the number
of ectopic beats associated with short-lasting coronary artery
occlusions by interruption of the cardio-cardiac sympathetic
reflex with afferent fibers running through the dorsal roots. It is
important to note, however, that surrogate endpoints for VF,
such as the absolute number of ectopic beats, may be misleading because spontaneous ventricular ectopy can be suppressed
by drugs without subsequent suppression of VF (2). Thus all
arrhythmia scaling systems should be approached with caution.
The critical determinant should be whether VF had or had not
occurred, because in the clinic, VF seldom (if ever) spontaneously reverts to a sinus rhythm. In addition, although the design
employed by Schwartz et al. (59) allowed internal control
analysis instead of group comparison as performed in the
present study; it is well documented (50) that brief periods of
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Fig. 4. Mean AP (A), heart rate (B), ST segment
elevation (C), and double product (D) at rest and
for the first 3 min of occlusion of the left main
coronary artery in control rats and rats that had
their T1-T5 dorsal root ganglia bilaterally excised
(Afferent-X). The hemodynamic parameters were
significantly reduced in the Afferent-X group during the occlusion. *P ⬍ 0.05, control vs. Afferent-X; significant group effect.
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CARDIAC SPINAL REFLEX AND ARRHYTHMIAS
ischemia interspaced with reperfusion alters the response to
subsequent ischemic events. Therefore, the findings of a higher
VAT in the deafferented group, reported in the present study,
extends the pioneering work of Schwartz et al. (59) to the
conscious animal in which clinically relevant ventricular tachyarrhythmias can be induced.
Activation of spinal afferents by a reduction in perfusion to
active skeletal muscle in man and rat elicits a pressor and
tachycardiac reflex commonly called the muscle metaboreflex
(3, 18). Similarly, myocardial ischemia elicited a metaboreflex-mediated increase in arterial pressure, heart rate, ST segment elevation, and double product (Fig. 4) in the present
study. Dorsal root section significantly reduced these hemodynamic responses to myocardial ischemia (Fig. 4). These results
contrast sharply with the results from Schwartz et al. (59) who
documented that C8-T5 dorsal root section produced only
minor changes in heart rate and blood pressure. It is likely that
the multiple short-lasting (5–90 s) occlusions of either the left
anterior descending or the circumflex coronary artery in the
previous study (59) compared with the up to 10 min of
occlusion of the left main coronary artery in the present study
as well as the confounding effects of anesthetic agents and
surgical trauma accounts for this difference.
Myocardial ischemia produces ventricular arrhythmias that
are reduced by surgical ablation of cardiac sympathetic nerves
in a variety of experimental and clinical models (19, 58, 62, 63,
65, 67, 75). Results from these studies and others (35, 45, 49)
AJP-Regul Integr Comp Physiol • VOL
document that ischemia-induced ventricular arrhythmias are
mediated, in part, by an excitatory cardio-cardiac reflex that
increases cardiac sympathetic efferent activity. For example, Schwartz and colleagues (47, 59) demonstrated that
myocardial ischemia provokes a powerful increase in cardiac sympathetic efferent activity that directly promotes
ventricular tachycardia. Furthermore, sympathetic nerve activity increases before the onset of ventricular tachyarrhythmias in conscious dogs (77). Taken together, data document
that cardiac sympathetic afferents are excited by ischemia
and elicit a cardio-cardiac sympathetic reflex (10, 46),
which plays a major role in the genesis of ventricular
arrhythmias (59). The cardio-cardiac sympathetic reflex, in
addition to mediating cardiac sympatho-excitation, inhibits
cardiac vagal efferent activity (low vagal activity is associated with ventricular arrhythmic events) (13, 61).
Limitations
The dorsal root ganglia contain cell bodies of fibers that
transmit sensory information from somatic and visceral receptive fields. Specifically, the dorsal roots from T1-T5 contain
spinal (sympathetic) afferent fibers with cardiac endings as
well as cutaneous and muscle endings (46). Dorsal root excision therefore interrupts both somatic and visceral input.
Schwartz et al. (59) documented that interruption of the somatic input does not account for the decrease in the number of
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Fig. 5. Mean AP (A), heart rate (B), ST segment
elevation (C), and double product (D) immediately
before the onset of sustained ventricular tachycardia
in control rats and rats that had their T1-T5 dorsal
root ganglia bilaterally excised (Afferent-X). Although mean AP and ST segment elevation were
not different between groups, heart rate and double
product were significantly lower in the Afferent-X
group. *P ⬍ 0.05, control vs. Afferent-X.
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CARDIAC SPINAL REFLEX AND ARRHYTHMIAS
Clinical Perspective
SCD causes more than 350,000 deaths annually in the
United States (1, 76, 78) and is most commonly caused by
ischemia-induced ventricular tachyarrhythmias that culminate
in VF (6, 28). Importantly, implantable cardioverter-defibrillators (ICD) reduce mortality in high-risk patients; however,
ICDs treat ventricular arrhythmias without preventing them
and can be proarrhythmic if patients sustain recurrent ICD
shocks. ICDs are also expensive and are associated with
morbidity from implantation complications as well as potential
mechanical dysfunction. Antiarrhythmic drugs are often used
for reducing SCD; however, the pharmacological approach to
antiarrhythmic therapy has serious problems. Most antiarrhythmic drugs are less effective and far more dangerous than once
believed (11, 12, 23, 54, 73) and are often poorly tolerated and
have serious side effects.
The proarrhythmic effects of ICDs and most currently available antiarrhythmic drugs, combined with the enormity of the
problem make it essential to investigate novel strategies for the
prevention of SCD. In this context, the present data strengthens
and supports the extensive clinical and preclinical evidence
that disruption of cardiac innervation either pharmacologically
with local anesthetics or antiadrenergic interventions such as
beta blockers or with surgical ablation of cardiac nerves are
therapeutic alternatives for the management of life-threatening
ventricular arrhythmias (4, 7, 8, 19, 29, 33, 44, 48, 51, 56, 60,
62– 64, 66, 67, 72, 75). Accordingly, cardiac spinal deafferentation may become an additional therapeutic option. For example, deafferentation by several specific procedures including
dorsal root entry zone lesions and thermocoagulation and
dorsal rhizotomy are currently in use for a variety of conditions
associated with intractable pain as well as over activity of
skeletal and smooth muscle associated with spinal cord injury.
Specifically, sacral deafferentation is effective to control autoAJP-Regul Integr Comp Physiol • VOL
nomic dysreflexia and spasticity in individuals with spinal cord
injury (31). Deafferentation was also effective for bilateral
intercostal neuralgia that developed following breast augmentation since the pain was completely relieved by T3-T5 dorsal
rhizotomies (22). Thus, disruption of spinal afferent fibers is a
well-tolerated, effective procedure with low complications for
several conditions. It is possible that similar procedures could
be used to reduce ventricular arrhythmias and SCD in high-risk
patients; however, additional studies are required to further
characterize the physiological responses to this procedure and
to determine whether this new approach is safe and efficacious
for the treatment of conditions associated with excess sympathetic activity.
GRANTS
This study was supported by National Heart, Lung, and Blood Institute
Grant HL-88615.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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