L.C. Weaver and C. Polosa (Eds.

)
Progress in Brain Research, Vol. 152
ISSN 0079-6123
Copyright r 2006 Elsevier B.V. All rights reserved

CHAPTER 18

Spinal cord injury alters cardiac electrophysiology

and increases the susceptibility to
ventricular arrhythmias

Heidi L. Collins1, David W. Rodenbaugh2 and Stephen E. DiCarlo1,

1
Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
2
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA

Abstract: The autonomic nervous system modulates cardiac electrophysiology and abnormalities of au-
tonomic function are known to increase the risk of ventricular arrhythmias. The abnormal and unstable
autonomic control of the cardiovascular system following spinal cord injury also is well known. For
example, individuals with mid-thoracic spinal cord injury have elevated resting heart rates, increased blood
pressure variability, episodic bouts of life-threatening hypertension as part of a condition termed auto-
nomic dysreflexia, and elevated sympathetic activity above the level of the lesion. Furthermore, cardio-
vascular morbidity and mortality are high in individuals with spinal cord injuries due to a relatively
sedentary lifestyle and higher prevalence of other cardiovascular risk factors, including obesity and di-
abetes. Therefore, spinal cord injury may alter cardiac electrophysiology and increase the risk for ven-
tricular arrhythmias. In this chapter, we discuss how the autonomic changes associated with cord injury can
influence cardiac electrophysiology and the susceptibility to ventricular arrhythmias.

Individuals with spinal cord injury in the cervical
and upper thoracic (T) segments (T1–T6) have
unstable arterial pressure and heart rate. In addi-
tion to other factors, the unstable arterial pressure
and heart rate after spinal cord injury enhances the
risk for blood pressure-related cardiovascular dis-
ease above levels seen in hypertensive subjects
(Rodenbaugh et al., 2003a). Thus, it is not sur-
prising that cardiovascular disease is a leading
cause of morbidity and mortality for individuals
with spinal cord injury. In this chapter, we will
discuss the impact of spinal cord injury on the
autonomic control of the circulation and its rela-
tionship to increased risk for cardiac arrhythmias.
An estimated 2 million individuals worldwide
live with spinal cord injuries. On average, 11,000
Corresponding author. Tel.: +(313) 577-1557;
Fax: +(313) 577-5494; E-mail: sdicarlo@med.wayne.edu
new injuries are reported each year in the United
States alone. Spinal cord injuries cost the United
States at least $9.7 billion per year for medical
care, equipment and disability support (DeVivo,
1997; Berkowitz et al., 1998). With the advances in
acute care and rehabilitation, the life expectancy of
individuals with spinal cord injury has increased to
near that for able-bodied individuals. However,
cardiovascular disease is now a leading cause of
death and morbidity for individuals with spinal
cord injury (Le and Price, 1982; Wicks et al.,
1983; Cardiovascular–Cardiopulmonary Second-
ary Disabilities, 1991; DeVivo et al., 1992, 1993;
Whiteneck et al., 1992; Frankel et al., 1998; Soden
et al., 2000). Cardiovascular morbidity and mor-
tality are high for individuals with spinal cord in-
juries, presumably due to a relatively sedentary
lifestyle and higher prevalence of other cardiovas-
cular risk factors, including obesity and diabetes

DOI: 10.1016/S0079-6123(05)52018-1 275

276

(Duckworth et al., 1980; Levi et al., 1995; Rodenbaugh et al., 2003a, b, c). This phenomenon
Karlsson, 1999). In fact, individuals with spinal is illustrated in Fig. 1 that shows the heart rate for
cord injury are at the lowest end of the human intact and cord-injured rats, recorded by radio-
fitness spectrum (Dearwater et al., 1986; Washburn telemetry, averaged over each week for 7 weeks
and Figoni, 1998). Similarly, cord-injured rats have (panel A) or for the entire 7 weeks of study (panel
lower levels of physical activity than healthy intact B). Animals with cord transection at T5 had
rats (Rodenbaugh et al., 2003a). Additionally, in- increased heart rates each week during the entire 7
dividuals with cord injury have blood lipid profiles weeks of study (panel A). Specifically, the average
characterized by elevated total cholesterol and heart rate was 19% higher in cord-injured rats
low-density lipoprotein cholesterol, and depressed during the entire 7 weeks of study (panel B).
high-density lipoprotein cholesterol, a lipid profile Numerous studies have documented that an
normally associated with, if not a direct result of, elevated heart rate is a strong risk factor for the
the sedentary lifestyle (Bauman et al., 1992, 1999; development of cardiovascular disease (Palatini
Cardus et al., 1992). There is a strong association and Julius, 1997, 1999; Julius et al., 1998). The
between low physical activity, increased sympa- elevated heart rates observed in individuals with
thetic nervous system activity, and cardiovascular mid-thoracic cord injury may be mediated by a
disease risk factors (Zimmet et al., 1991; Collins reflex compensatory mechanism to offset the de-
et al., 2000). Importantly, increased physical ac- creased stroke volume (Hjeltnes, 1977; Hopman
tivity lowers sympathetic nerve activity (DiCarlo et al., 1993a). The lower stroke volume has been
et al., 1997) and cardiovascular disease risk factors
(Jennings et al., 1984; Collins et al., 2000; DiCarlo
et al., 2002). Therefore, exercise with the arms is
often recommended for individuals with cord in-
jury, based on studies demonstrating improve-
ments in aerobic capacity and lipoprotein profiles
(DiCarlo, 1982, 1988; DiCarlo et al., 1983; Glaser,
1985; Hoffman, 1986; Hooker and Wells, 1989).
In fact, the Center for Disease Control has rec-
ommended further research to evaluate the effica-
cy of exercise to prevent the development of
cardiovascular disease in individuals with cord
injury (Cardiovascular–Cardiopulmonary Second-
ary Disabilities, 1991). It is interesting to speculate
that one mechanism contributing to the improved
cardiopulmonary status after exercise in indi-
viduals with spinal cord injury (DiCarlo, 1982;
DiCarlo et al., 1983) may be a reduced incidence
and/or severity of cardiac arrhythmias.
Cord-injured individuals have distinct hemody-
namic responses to a variety of activities of daily
living. For example, it is well established that Fig. 1. Average heart rate for intact and cord-injured rats, re-
individuals with mid-thoracic cord injury have corded by radio-telemetry, each week for 7 weeks (panel A) and
elevated heart rates and lower stroke volumes at the heart rates averaged during the entire 7 weeks of the study
rest and during activity than able-bodied indi- (panel B). Heart rate was higher in the cord-injured rats at every
time point during the 7 weeks of the study. Specifically, heart
viduals (Jacobs et al., 2002). Similarly, rats with
rate was 19% higher in cord-injured rats during the entire 7
cord injury at the 5th thoracic segment (T5) have weeks of the study (panel B). In this and subsequent figures,
elevated heart rates (Krassioukov and Weaver, variability is indicated by the standard error of the mean
1995; Maiorov et al., 1997; Mayorov et al., 2001;

Pp0:05:

attributed to reduced venous return from the in-
active regions below the level of the injury due to
loss of supraspinal control of sympathetically me-
diated veno- and vasoconstriction (Kinzer and
Convertino, 1989; Hopman et al., 1993b). The loss
of supraspinal control of sympathetically mediated
veno- and vasoconstriction impairs the ability to
effectively distribute blood throughout the vascu-
lar system and results in venous pooling. Preven-
tion of venous pooling with an external ‘‘muscle
pump’’ using transcutaneous electrical stimulation
markedly enhances stroke volume in cord-injured
individuals (Davis et al., 1990). Cardiac output,
the volume of blood pumped by the heart each
minute, is the product of heart rate and stroke
volume and is lower in cord-injured people (Jacobs
et al., 2002).
In able-bodied individuals the average heart rate
at rest is 60–80 beats per minute. As noted above,
heart rate is significantly higher in individuals with
mid-thoracic cord injury. During emotional ex-
citement or muscular activity, heart rate increases
reaching values as high as 220 beats per minute
minus the age of the individual. The maximum
heart rate is not altered in individuals with
mid-thoracic cord injury (Jacobs et al., 2002). The
increase in heart rate is mediated, mainly, by chang-
es in the autonomic nervous system. The process
of excitation of the heart originates in the sino-
atrial node, the intrinsic pacemaker of the heart,
located in the right atrium. These cells depolarize
spontaneously and generate action potentials at an
intrinsic rate of about 100 per minute (Jose, 1966;
Katona et al., 1982). The sinoatrial node is under
the direct influence of the sympathetic and para-
sympathetic divisions of the autonomic nervous
system. In general, the sympathetic division of the
autonomic nervous system increases heart rate by
increasing the rate at which the sinoatrial node
generates action potentials, whereas the parasym-
pathetic division of the autonomic nervous system
decreases heart rate by decreasing the rate of ac-
tion potential generation by the sinoatrial node.
Usually, changes in heart rate involve the recipro-
cal actions of the two divisions of the autonomic
nervous system. Specifically, an increased heart
rate is mediated by a reduction in parasympathetic
activity and a concomitant increase in sympathetic
277
activity whereas a decreased heart rate is mediated
by an increase in parasympathetic activity and a
concomitant decrease in sympathetic activity.
Overactivity, or dominant activity in the cardiac
parasympathetic nerves can produce or contribute
to a variety of brady-arrhythmias whereas over-
activity or dominant activity of the cardiac sym-
pathetic nerves can produce or contribute to a
variety of tachy-arrhythmias (Katz, 1992). In rest-
ing able-bodied individuals parasympathetic activ-
ity dominates. Thus, when both divisions of the
autonomic nervous system are blocked (by drugs
such as atropine for parasympathetic and prop-
ranolol for sympathetic) in resting able-bodied
individuals, the heart rate increases to approxi-
mately 100 beats per minute (Jose, 1966; Katona
et al., 1982). This increase in heart rate following
complete autonomic nervous system blockade doc-
uments the dominance of the parasympathetic sys-
tem on resting heart rate. The prevailing heart rate
after block of both sympathetic and parasympa-
thetic cardiac influences is called the intrinsic heart
rate. Importantly, because the cardiac parasym-
pathetic fibers never pass through the spinal cord,
spinal cord injury does not interrupt cardiac para-
sympathetic activity. Cardiac parasympathetic
fibers originate in the dorsal motor nucleus of
the vagus and the nucleus ambiguus in the medulla
oblongata (Loewy and Spyer, 1990) and travel in
the vagus nerve to the heart. Subsequently, these
fibers synapse with postganglionic cells on the
epicardial surface or within the walls of the heart
near the sinoatrial node and atrioventricular node.
In contrast, spinal cord injury above the 1st
thoracic segment (T1) disrupts central control of
preganglionic cardiac sympathetic activity. Specif-
ically, preganglionic cardiac sympathetic fibers
originate in the intermediolateral cell column of
the upper five or six thoracic segments of the spinal
cord (Bonica, 1968). These fibers exit the spinal
cord through the white communicating rami and
enter the paravertebral chains of ganglia. The
cardiac preganglionic and postganglionic neurons
synapse in the middle cervical and upper thoracic
paravertebral ganglia, especially the stellate
ganglion (Bonica, 1968). Cervical and upper tho-
racic spinal cord injury disrupts the interaction
of the cardiac sympathetic and parasympathetic
278
innervation. Disruption of this balance may have a
profound influence on cardiac rate, performance
and rhythm. For example, the higher heart rates
observed in individuals and animals with mid-
thoracic cord injury suggest higher cardiac sym-
pathetic activity or lower cardiac parasympathetic
activity. To test this hypothesis we measured heart
rate in intact rats and rats with cord injury
at T5 under normal resting conditions and
during ganglionic blockade achieved by intrave-
nous administration of hexamethonium chloride.
Hexamethonium chloride abolishes postganglionic
sympathetic and parasympathetic nervous system
activity and reduces arterial pressure and heart
rate slightly in intact rats and more substantially in
cord-injured rats. Resting heart rate was signifi-
cantly higher in injured rats and decreased signif-
icantly more in response to ganglionic blockade.
Figure 2 presents heart rate before and after
ganglionic blockade in intact and cord-injured
rats. Ganglionic blockade reduced heart rate more
in injured rats compared with intact rats (36% vs.
9%, respectively). These findings are consistent
with the idea that an increase in sympathetic ac-
tivity above the level of the lesion in cord-injured
rats contributes to a greater tonic sympathetic
support of heart rate.
Elevations in cardiac sympathetic activity or
reductions in cardiac parasympathetic activity
Fig. 2. Heart rate before (control) and after ganglionic block-
ade (Gag-X) in intact and cord-injured rats. Ganglionic block-
ade (equivalent to elimination of all neural input to the heart)
reduced heart rate more in cord-injured rats than in intact rats
(36% vs. 9%, respectively).
increase the risk for the development of ventricu-
lar arrhythmias and sudden cardiac death
(Schwartz and Stone, 1980; Schwartz et al.,
1993). Therefore, the elevated heart rates and in-
creased cardiac sympathetic activity in individuals
with mid-thoracic cord injury (Karlsson et al.,
1998; Rodenbaugh et al., 2003b) may result in an
increased mortality associated with changes in
cardiac electrophysiology and the incidence of
arrhythmias. In fact, it has recently been docu-
mented that rats with cord transection at the 5th
thoracic segment have a lower electrical stimula-
tion threshold to induce cardiac arrhythmias
(Rodenbaugh et al., 2003b, c).
Arterial baroreceptors, located in the aortic arch
and carotid sinuses, have a profound influence on
cardiac rate, performance, and rhythm by reflexly
altering cardiac sympathetic and parasympathetic
activity. The arterial baroreceptors respond to a
reduction in arterial pressure by decreasing activity
of the parasympathetic nerves and increasing
activity of the sympathetic nerves. This imbalance
of the autonomic nervous system in favor of sym-
pathetic dominance can lead to tachy-arrhythmias.
In contrast, the arterial baroreceptors respond to
an increase in arterial pressure by increasing
activity of the parasympathetic nerves and
decreasing activity of the sympathetic nerves. This
imbalance favoring parasympathetic dominance
can lead to brady-arrhythmias. Arterial pressure is
usually lower and unstable after cervical and upper
thoracic spinal cord injury. Hypotension occurs
immediately after the injury because of loss of
tonic supraspinal excitatory drive to spinal
sympathetic neurons (Calaresu and Yardley,
1988). Subsequently, resting arterial pressure
returns toward normal. However, episodic hyper-
tension often develops as part of the condition
termed autonomic dysreflexia (Naftchi, 1990;
Mathias and Frankel, 1992). In addition, activi-
ties of daily living produce large variations of
blood pressure in individuals with cord injury
(Stiens et al., 1995; Faghri et al., 2001). This is due,
in part, to the fact that arterial baroreflex control
of the sympathetic nervous system is lost below the
level of the lesion, resulting in reduced buffering of
changes in arterial pressure. Thus, individuals and
animals with spinal cord injury have increased
 279

blood pressure variability after mid-thoracic cord
injury (Rodenbaugh et al., 2003a). Increased blood
pressure variability and heart rate significantly in-
crease the risk of cardiovascular diseases (Rizzoni
et al., 1992; Stevenson et al., 1997; Julius and
Valentini, 1998). These risk factors are highly cor-
related with end organ damage, as well as vascular
structure changes and an increased incidence of
myocardial infarction, stroke, and cardiac ar-
rhythmias (Frattola et al., 1993; Stamler et al.,
1993; Palatini and Julius, 1997, 1999). The in-
creased blood pressure variability mediates chang-
es in arterial baroreceptor activity that reflexly
alters cardiac sympathetic and parasympathetic
activity and profoundly affects cardiac rate, per-
formance, and rhythm. Importantly, cord-injured
rats have increased blood pressure-related cardio-
vascular disease risk factors (Rodenbaugh et al.,
2003a). For example, Fig. 3 presents the average
systolic blood pressure standard deviation (SBP-
SD) for intact and cord-injured rats each week for
7 weeks (panel A) and SBP-SD averaged over the
entire duration of the study (panel C). Mid-
thoracic cord injury significantly increased SBP-
SD each week for the entire 7 weeks of the study.
Specifically, SBP-SD was 22% higher in the in-
jured versus intact rats over the entire 7 weeks
(panel C). Similarly, the average diastolic blood
pressure standard deviation (DBP-SD) for intact
and cord-injured rats was examined (panels B and
D) and cord injury increased DBP-SD during the
entire 7 weeks of the study. Specifically, DBP-SD
was 13% higher in the injured versus intact rats
during the entire 7 weeks (panel D). Taken to-
gether, these data suggest that the loss of arterial
baroreflex control of the autonomic nervous sys-
tem below the level of the lesion increases arterial
blood pressure variability.
As noted above, cardiac tachy-arrhythmias are
associated with elevations of cardiac sympathetic
efferent activity (Schwartz and Stone, 1980, 1982).
Cardiac a- and b-adrenergic receptors mediate the
response to cardiac sympathetic stimulation. b-
Adrenergic receptor blockade, which reduces the

Fig. 3. Systolic blood pressure standard deviation (SBP-SD) and diastolic blood pressure deviation (DBP-SD) for intact and cord-
injured rats, averaged each week for 7 weeks (panels A, B) and averaged over the entire duration of the study (panels C, D). Spinal cord
injury significantly increased SBP-SD and DBP-SD. Specifically, SBP-SD was 22% higher in the injured versus intact rats over the
entire 7 weeks (panel C) and DBP-SD was 13% higher in the injured vs. intact rats over the entire 7 weeks (panel D)
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280
effect of cardiac sympathetic efferent activity, has
been shown to reduce cardiovascular mortality
(Frishman, 1992). The sympathetic nervous system
can affect the generation and conduction of action
potentials in the heart by activating mainly b-ad-
renergic receptors (Berne and Levy, 2001). b-Ad-
renergic receptor stimulation, which increases
intracellular cAMP, increases heart rate, atrioven-
tricular nodal conduction and contractile force,
and shortens atrial and ventricular refractoriness
(Murray and Roden, 1996). In addition, it en-
hances the plateau phase of the action potential by
increasing current through L-type Ca2+ channels
while repolarization is accelerated due to an in-
crease in both the delayed rectifier current and the
chloride current (Murray and Roden, 1996). Thus,
b-adrenergic receptor stimulation may shorten or
prolong action potential duration depending on
which of the currents predominate. b-Adrenergic
receptor stimulation also causes more rapid pace-
maker activity in the sinus node by its action on
diastolic currents (Murray and Roden, 1996). a-
Adrenergic receptor stimulation enhances cardiac
contractility due to Ca2+ influx (Berne and Levy,
2001). Furthermore, adrenergic stimulation en-
hances the development of after-depolarizations
that lead to electrocardiogram (ECG) complexes
termed triggered beats (Katz, 1992). In this situ-
ation, multiple ionic mechanisms are involved, and
elevated intracellular calcium is a common feature.
Adrenergic stimulation results in a reduction of the
electrical stimulus threshold to induce ventricular
fibrillation as well as an increase in the likelihood
of spontaneous ventricular arrhythmias. b-Ad-
renergic receptor blockade and enhanced para-
sympathetic tone inhibit these effects and are
known to be protective against ventricular tachy-
arrhythmias and sudden death (Engel, 1978; Zipes,
1991; Wharton et al., 1992; Schwartz et al., 1993).
Thus, interventions that reduce sympathetic activ-
ity or enhance parasympathetic activity may be
useful in preventing deadly tachy-arrhythmias.
Spinal cord injury, depending on the specific site
of the lesion, may affect sympathetic and para-
sympathetic activity in a manner that promotes
arrhythmias.
In addition to transmembrane signals that alter
ionic currents over the time course of seconds,
adrenergic signals alter cardiac electrophysiology
over the time course of hours to days by altering
transcription of genes encoding ion channels and
calcium-regulating proteins. For example, suscep-
tibility to cardiac arrhythmias may increase by al-
tering the expression of specific genes encoding
proteins critical to myocyte calcium homeostasis
[the sarco(endo)plasmic reticulum Ca2+ ATPase
(SERCA), the Na+/Ca2+ exchanger encoded by
the NCX1 gene, and the L-type calcium channel]
in a manner that will favor increasing intracellular
Ca2+ (Rodenbaugh et al., 2003c). The ability of
cardiac myocytes to maintain cytosolic Ca2+ with-
in a tightly controlled range is important to pre-
vent cardiac electrical disturbances. Disturbances
in Ca2+ homeostasis are closely related to cardiac
electrophysiological events. The Na+/Ca2+ ex-
changer and the L-type calcium channel provide
the primary calcium efflux and influx pathways,
respectively. SERCA is the predominant pathway
through which cytosolic calcium is sequestered.
Signaling through a- and b-adrenergic receptors
modulates calcium homeostasis by altering the ex-
pression of these calcium regulatory proteins. For
example, signaling through a- and b-adrenergic
receptors coordinately regulates the expression of
the a 1C-subunit of the L-type calcium channel
and the Na+/Ca2+ exchanger by activating pro-
tein kinase A and protein kinase C pathways
(Golden et al., 2000, 2002). Specifically, b-ad-
renergic receptor activation in vitro increases the
expression of the L-type Ca2+ channel and NCX1
genes, whereas a-adrenergic signaling reduces their
mRNA levels (Golden et al., 2000, 2001, 2002).
Several facts have been well documented. The
autonomic nervous system modulates cardiac
electrophysiology and abnormalities of autonom-
ic function can increase the risk of cardiac
arrhythmias. Furthermore, autonomic control of
the cardiovascular system is abnormal and unsta-
ble following spinal cord injury. For example, in-
dividuals with spinal cord injury have elevated
heart rates, increased blood pressure variability,
elevated sympathetic activity above the level of the
lesion, and episodic bouts of life-threatening hy-
pertension as part of a condition termed auto-
nomic dysreflexia. Autonomic dysreflexia occurs in
as many as 85% of individuals with spinal cord
 281

injuries above the 6th thoracic segment and is

characterized by severe hypertension (Lee et al.,
1995). If not prevented or treated promptly, the
hypertension may produce cerebral and sub-
arachnoid hemorrhage, seizures, renal failure, car-
diac arrhythmias, and may lead to death (McGuire
and Kumar, 1986). An example of autonomic
dysreflexia in rats is presented in Fig. 4, illustrating
an analog recording of arterial pressure, ECG, and
heart rate responses to colon distension in a quad-
riplegic rat (Collins and DiCarlo, 2002). Colon
distension produced an increase in arterial pres-
sure, bradycardia, and arrhythmias. This observa-
tion demonstrates that abnormal control of the
cardiovascular system after spinal cord injury can
increase the susceptibility to cardiac arrhythmias.
Autonomic dysreflexia is the second most com-
mon long-term secondary medical complication
associated with cord injury and thus is a major
health concern (McKinley et al., 1999). In fact,
autonomic dysreflexia is the most prominent life-
threatening situation for individuals with spinal
cord injury (Comarr and Eltorai, 1997). The long-
term consequence of repeated episodes of severe
hypertension has yet to be determined, however, it
is well documented that increased blood pressure
variability is a significant cardiovascular disease
risk factor (Frattola et al., 1993; Collins et al.,
2000). Thus, the incidence of cardiac arrhythmias
may be increased in individuals with spinal cord
injury due to the unstable arterial blood pressure.
In support of this concept, there are a large
number of case reports documenting cardiac
arrhythmias in individuals with spinal cord injury
(Guttmann and Whitteridge, 1947; Frankel et al.,
1975; Colachis and Clinchot, 1997). For example,
as early as 1947, Guttmann and Whitteridge re-
ported premature atrial and ventricular contrac-
tions as well as changes in the amplitude of the
T-waves in individuals with spinal cord injuries Fig. 4. Analog recording of arterial pressure, ECG, and heart
during urodynamic testing. Arrhythmias have also rate response to colon distension (50 mmHg for 1 min) in one
quadriplegic rat. Dashed line indicates the onset of colon dis-
been observed in a woman with a spinal lesion at
tension. Colon distension produced pressor and bradycardic
T3 during labor (Guttmann et al., 1965). Prema- responses. Of particular interest are the arrhythmias produced
ture ventricular contractions and atrio-ventricular by colon distension (insert). Reprinted with permission from
dissociation are common when individuals with spi- Collins and DiCarlo (2002).
nal cord injuries have distended bladders (Guttmann
and Whitteridge, 1947) and asystole as well as
other arrhythmias have been reported during
282
tracheal suctioning (Frankel et al., 1975) and
autonomic dysreflexia. Profound bradycardia is a
common complication in the early post-traumatic
period following cervical spinal cord damage. It is
thought to be due to temporary inactivity of the
sympathetic nervous system after separation from
supraspinal control, coupled with unopposed
parasympathetic dominance because of parasym-
pathetic, vagus nerve sparing (Mathias, 1976;
Piepmeier et al., 1985; Lehmann et al., 1987; Bravo
et al., 2004). Hypoxia, hypo-ventilation, and trache-
al suctioning appear to intensify the bradycardia. In
animals, acute spinal cord transection produces a
variety of arrhythmias (Greenhoot et al., 1972).
Several human studies have documented ECG
characteristics of individuals with spinal cord in-
jury. Blocker et al. (1983) analyzed the resting
ECG of 98 individuals with chronic cord injury
and compared their findings with results from two
studies of healthy able-bodied individuals. The in-
vestigators reported that ECG abnormalities were
more prevalent in the individuals with cord injury.
The mean age of the individuals with cord injury
was 47 years and more than half of the individuals
had sustained their injury before the age of 40. The
most common ECG abnormalities were ST seg-
ment depression and T-wave inversion. Axis devi-
ation, ventricular conduction delays, frequent
premature ventricular contractions, and low QRS
amplitude were also recorded. As might be ex-
pected, ECG abnormalities were most prevalent in
the 50–59 age group. The sample contained an
equal number of subjects with cervical and tho-
racic cord injury. ECG abnormalities were most
often recorded when the injury was cervical. The
incidence of ECG abnormalities did not relate to
the time interval after the cord injury. Individuals
with lumbar spinal cord injury had no ECG ab-
normalities. Lehmann et al. (1989) also analyzed
the ECG of individuals with spinal cord injury.
These investigators reported altered ventricular
depolarization in individuals with cervical spinal
cord injury. These results were confirmed recently
(Marcus et al., 2002). The ECG abnormalities
consisted of an upwardly concave ST-segment.
In contrast to the reports cited above, Prakash
et al. (2002) documented that the prevalence of
ECG abnormalities was the same for able-bodied
individuals and individuals with spinal cord
injury. These investigators examined the ECG of
26,734 able-bodied male veterans with a mean age
of 56 years and compared the data with the ECG
of 654 individuals with SCI with a mean age of 50
years. Similarly, Leaf et al. (1993) studied 47 in-
dividuals with chronic SCI (35–3605 days post-in-
jury). Twenty-five individuals were classified as
paraplegic (mean age 39 years). No differences
were recorded in the incidence of abnormalities
between the individuals with paraplegia and quad-
riplegia. Thus, the data regarding ECG abnormal-
ities associated with SCI are equivocal.
Two reported studies tested the effect of spinal
cord injury at T4 on cardiac electrophysiology and
the susceptibility to ventricular arrhythmias
(Rodenbaugh et al., 2003a, c). In the first study,
conscious female hypertensive cord-injured rats
had a significantly lower electrical stimulation
threshold to induce ventricular arrhythmias com-
pared to intact rats. The protocol used to induce
arrhythmias is presented in Fig. 5. Ventricular
arrhythmia was defined as sustained ventricular
tachycardia resulting in a reduction in arterial
pressure. The intensity of current required to
cause a ventricular arrhythmia was 62% lower in
cord-injured rats compared with intact rats. Cord-
injured rats also had a 35% lower effective refrac-
tory period compared to intact rats. Associated
with the increased susceptibility to ventricular
arrhythmias was a significantly higher resting
heart rate and cardiac sympathetic tone (as deter-
mined by the effect of propranolol on heart rate
after the administration of atropine (Chen and
DiCarlo, 1997). Triggered beats occur more fre-
quently in the presence of increased heart rate
(Rosen and Reder, 1981). The enhanced cardiac
sympathetic activity in the cord-injured rat may be
the cause of increased susceptibility to ventricular
arrhythmias. In this first study, female spontane-
ously hypertensive rats were studied because they
have elevated cardiac sympathetic activity
(Chandler and DiCarlo, 1998) and are susceptible
to cardiac arrhythmias. In the second study
(Rodenbaugh et al., 2003c), changes in cardiac
calcium regulatory proteins (Fig. 6), cardiac elect-
rophysiology parameters, and the susceptibility to
ventricular arrhythmias were examined in intact
 283

Fig. 5. Analog recording of arterial pressure and the ECG during step increases in current delivered to the heart in a conscious cord-
injured hypertensive rat. A MacLab programmable stimulator delivered 10 s trains of pulses (frequency 50 Hz and duration of 10 ms).
The current was increased every 10 s in 10 mA increments. Ventricular arrhythmia was identified by both the ECG as rapid, wide QRS
complexes and a decrease in arterial pressure to 40 mmHg (inset). In this animal, the threshold current required to induce the
arrhythmia was 100 mA. Normal sinus rhythm reappears upon termination of the stimulation (not shown). Reprinted with permission
from Rodenbaugh et al. (2003b).

and cord-injured rats (Fig. 7). Mid-thoracic cord
injury was associated with alterations in the
abundance of cardiac calcium regulatory proteins.
For example, cord injury increased the relative
protein expression of SERCA2 (45%) and the
Na+/Ca2+ exchanger (40%), whereas relative
protein expression of phospholamban was signif-
icantly decreased (28%, Fig. 6). It is well doc-
umented that reductions in phospholamban and/
or increases in SERCA protein abundance result
in an increased sarco(endo)plasmic reticulum
calcium load (Ji et al., 2000). The sarco(endo)-
plasmic reticulum calcium overload may produce
spontaneous calcium release, thereby leading to
ectopic activity. Importantly, these molecular
changes were associated with enhanced cardiac
electrophysiology parameters and a reduced elec-
trical stimulation threshold to induce ventricular
arrhythmias. The cord-injured rats had a reduced
electrical stimulation threshold to induce ventricu-
lar arrhythmias (48%, Fig. 7) as well as shorter
atrial-ventricular interval, sinus node recovery
time and Wenckebach cycle length. In this study,
mean arterial pressure was not significantly differ-
ent between the intact and cord-injured rats.
However, injured rats had significantly higher
284
Fig. 6. Western blots for sarco(endo)plasmic reticulum Ca2+
ATPase (SERCA; A), phospholamban (PLM; B), and sodium
calcium exchanger (NCX; C) using the hearts of two intact and
two cord-injured male Wistar rats. Quantified relative abun-
dance for each protein of interest in intact (n ¼ 8) and cord-
injured (n ¼ 8) rat hearts. Spinal cord injury increased the rel-
ative abundance of SERCA (by 45%) and Na/Ca exchanger (by
40%) with a concomitant decrease in phospholamban (28%);


Pp0:05; intact vs. injured rats. Reprinted with permission
from Rodenbaugh, et al. (2003c).
heart rates (Mayorov et al., 2001; Jacobs et al.,
2002; Rodenbaugh et al., 2003b, c).
These results were consistent with clinical
reports suggesting an increased susceptibility to
cardiac arrhythmias (Guttmann and Whitteridge,
1947; Frankel et al., 1975; Colachis and Clinchot,
1997) as well as alterations in the ECG of indi-
viduals with spinal cord injuries (Lehmann et al.,
1989; Marcus et al., 2002). The results were also
consistent with a cardiac sympatho-excitation in
rats with mid-thoracic cord injury (Maiorov et al.,
1997; Rodenbaugh et al., 2003b) and humans with
Fig. 7. Electrical stimulation threshold to induce ventricular
arrhythmias in intact (n ¼ 10) and cord-injured rats (n ¼ 6).
Spinal cord injury significantly reduced the stimulation thresh-
old by 48%. The stimulation threshold was not significantly
different in the rats that served as time controls.
Pp0:05; in-
tact vs. injured rats. Reprinted with permission from Rodenb-
augh et al. (2003c).
a similar injury (Davis and Shephard, 1988; Kinzer
and Convertino, 1989; Jacobs et al., 2002).
Intravenous epinephrine in humans mimicked the
effects of mid-thoracic spinal cord injury on heart
rate, effective refractory period and atrioventricu-
lar conduction (Morady et al., 1988). A b-ad-
renergic receptor antagonist blocked these effects
of epinephrine. Conversely, perturbations that
lower sympathetic activity and/or raise parasym-
pathetic activity slow the conductive properties
and intrinsic excitability of the heart (Stein et al.,
2002; Such et al., 2002). Taken together, these re-
sults suggest that the increased susceptibility to
ventricular arrhythmias in cord-injured rats may
be due, in part, to increased cardiac sympathetic
activity. The increased cardiac sympathetic activ-
ity, higher heart rates, and changes in calcium
regulatory proteins in the cord-injured rats favor
conditions of calcium overload that increases the
likelihood for ventricular arrhythmias.
Conclusion
Individuals with spinal cord injury have unstable
arterial pressure and heart rate due to profound
changes in the autonomic nervous system. Fur-
thermore, the autonomic nervous system modu-
lates cardiac electrophysiology and abnormalities
of autonomic function can increase the risk of

ventricular arrhythmias. Recent data suggest an
increased susceptibility to ventricular arrhythmias
with concomitant changes in cardiac electrophys-
iology parameters and the abundance of calcium
regulatory proteins in a conscious chronic model
of mid-thoracic spinal cord injury. These effects
may be mediated by an increased cardiac sympa-
thetic activity. It is interesting to speculate that
these cardiac changes contribute, in part, to the
fact that cardiovascular disease is a leading cause
of death for individuals with chronic spinal
cord injury.
Acknowledgments
We gratefully acknowledge the expert technical
assistance of Dustin G. Nowacek. This work was
supported, in part, by the National Heart Lung
and Blood Institute Grant HL-74122.
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