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(Circulation. 1997;96:1337-1342.)
© 1997 American Heart Association, Inc.
Articles |
Heterogeneous Sympathetic Innervation in German Shepherd Dogs With Inherited Ventricular Arrhythmia and Sudden Cardiac Death
From the Cardiovascular Research Institute, School of Medicine, University of California at San Francisco (M.W.D., R.J.L., P.C.U., M.C.C., C.A.S.), and the Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M.).
Correspondence to Michael W. Dae, MD, Box 0252, Room L-340, University of California at San Francisco, San Francisco, CA 94143. E-mail michael_dae{at}radmac1.ucsf.edu
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Abstract |
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Background Recently, a colony of German shepherd dogs with inherited spontaneous cardiac arrhythmias and associated sudden death has been developed and characterized. Due to the median age of onset of the arrhythmia (4.5 months), the tendency for the arrhythmia to occur during REM sleep or after exercise, and the absence of structural heart disease, we hypothesized a developmental abnormality of the sympathetic innervation to the heart.
Methods and Results We studied 11 dogs from this colony, ranging in age from 6 months to 6 years, and four 7-month-old German shepherd dogs unrelated to the colony as controls. We imaged the distribution of functional myocardial sympathetic innervation and perfusion with [123I]metaiodobenzylguanidine (MIBG) and 201Tl, respectively. Sympathetic nerve distribution was evaluated morphologically by immunocytochemical localization of tyrosine hydroxylase. All of the hearts showed evidence of a regional decrease in MIBG uptake, ranging from 5.3% to 53.4% of the myocardium, whereas control dogs showed homogeneous MIBG uptake. Immunocytochemical studies on sections from regions with decreased MIBG uptake showed a striking paucity of nerves compared with regions with normal MIBG uptake, confirming denervation. When the dogs were grouped into those with (n=6) and without (n=5) evidence of ventricular tachycardia on ambulatory ECG, the group with ventricular tachycardia showed 35±16.5% denervation, whereas the group without ventricular tachycardia showed 12±5.6% denervation (P<.02).
Conclusions Abnormal heterogeneous sympathetic innervation exists in these dogs with inherited ventricular arrhythmia and sudden cardiac death. Mechanisms relating the presence and extent of regional denervation to the incidence of ventricular arrhythmia remain to be defined.
Key Words: arrhythmia • catecholamines • imaging • nervous system • scintigraphy
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Introduction |
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Despite significant advances in experimental and clinical electrophysiology, sudden cardiac death continues to be a major clinical problem and a pathophysiological enigma.1 2 Sudden cardiac death usually occurs in patients with structural heart disease,2 3 whereas patients with structurally normal hearts generally have a lower risk of death. However, patients with polymorphous VT or ventricular fibrillation, normal cardiac function, and a high incidence of sudden death have recently been described.4 5 6
Experimental studies of the pathogenesis of potentially lethal ventricular arrhythmias are limited by our current models of sudden death. Experimental models of VT and sudden death focus primarily on models of myocardial infarction and ischemia. Few genetic models of VT and sudden death exist. Recently, a colony of German shepherd dogs with inherited spontaneous cardiac arrhythmias and associated sudden death has been developed and characterized.7 The median age of onset of the arrhythmia (4.5 months), the tendency for the arrhythmia to occur during REM sleep8 or after exercise, and the absence of structural heart disease suggest a developmental abnormality of the autonomic innervation to the heart.
To determine whether myocardial sympathetic imbalance may be present in this colony of German shepherds, we studied myocardial sympathetic innervation functionally using MIBG imaging. Radiolabeled MIBG is taken up by sympathetic nerve endings and provides a map of functional sympathetic nerve density.9 We compared the distribution of MIBG with the distribution of myocardial perfusion imaged with 201Tl. We also correlated the distribution of MIBG with corresponding tissue sections showing immunohistochemical localization of tyrosine hydroxylase in sympathetic nerves.
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Methods |
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Study Population
We studied 11 dogs from this colony, ranging in age from 6 months to 6 years (mean, 27.1±27.8 months). In addition, we studied 4 purebred, 7-month-old German shepherd dogs that were unrelated to the colony as controls. The imaging and histological studies were performed and analyzed without knowledge of previous findings from ambulatory ECG recordings, which were available for each animal. The ambulatory ECG data were subsequently used to group the animals according to the presence or absence of VT for comparison to the image findings.
Ambulatory ECG and Electrocardiography
Serial 24-hour ambulatory ECG monitoring was performed in
all dogs. ECG monitoring was performed biweekly from 6 weeks of age
until 
8 months of age in the dogs from the colony. Control dogs were
monitored every 4 weeks from 6 weeks of age to 7 months. Ambulatory
recordings were obtained with standard cassette recorders
(Del Mar Avionics) and the XYZ lead configuration. The ECG patches were
secured with a small drop of tissue adhesive, and the lead wires and
recorder were secured with a vest and elastic wraps around the
thorax between the front limbs and the cranial abdomen. All
recordings were begun between 6 and 9 AM. Because
of the polymorphic configuration of the ventricular
arrhythmias, short coupling intervals (frequently <200 ms),
large T waves, high sinus heart rate, and the rapid rates of the
nonsustained runs of VT (>400 bpm), characterization of
ventricular arrhythmias with automated
analysis of the recordings was not possible.
Consequently, all recordings were analyzed manually by
individuals experienced in the interpretation of the canine ECG. PVCs
were counted and expressed as PVCs per hour. VTs, defined as 4 PVCs
in a row, were counted and expressed as runs of VT per 24 hours. We
selected the recording with the greatest number of ectopic
beats for analysis and characterization.
For each animal, 12 surface ECG leads were recorded during anesthesia for the assessment of QT intervals.
Imaging Protocol
At the time of study, the dogs were anesthetized with
pentobarbital, intubated, and ventilated with a Harvard respirator.
[123I]MIBG (6 mCi [222 MBq]) was injected
intravenously, followed 3 hours later by the injection of 2
mCi (74 MBq) of 201Tl. The animals were then killed with an
injection of saturated potassium chloride. The hearts were excised and
sliced into 1-cm transverse sections. A thin, 2- to 3-mm layer was
removed from each transverse section, fixed in 10% buffered formalin,
then stored at 4°C in 30% sucrose/phosphate buffer for subsequent
immunohistochemistry (see below). The remaining slices were imaged with
a Siemens LEM portable gamma camera fitted with a 20° slant-hole
collimator and interfaced to a PC-based computer acquisition system
(Harpootlian Associates). Two sequential 5-minute images were acquired
with a 20% window set at 159 keV for 123I and 80 keV for
201Tl. The scintigraphic method for detecting regional
sympathetic innervation with MIBG has been validated
previously.9 All procedures were approved by the Committee
on Animal Research, Office of Research Affairs, University of
California, San Francisco.
Image Analysis
Color functional maps were generated from the images of
myocardial slices to show the relative distributions of MIBG and
thallium as previously described.9 By this method, areas
showing a balanced distribution of MIBG and thallium (normal
innervation) are color coded red. Areas showing reduced MIBG relative
to thallium (denervation) are yellow to green. Areas showing increased
MIBG relative to thallium are purple to blue. Increased MIBG relative
to perfusion has been seen in the right ventricle of dogs and
correlates with the increased norepinephrine content
sometimes seen in the right ventricle compared with the left
ventricle.9 The areas of denervation and normally
innervated myocardium on the color maps were
traced onto acetate sheets. The outlined images were digitized with a
CCD video camera (MCID Systems). The total area of denervation and
normally innervated myocardium was then
measured for each heart, from which the percent denervated
myocardium (area of denervation/total area) was calculated.
In addition, the functional maps were used to guide sampling of tissue
from regions with reduced and normal MIBG uptake for comparison with
histology of sympathetic nerves.
Immunohistochemistry
To assess sympathetic nerve density, immunocytochemical
localization of tyrosine hydroxylase was done.10 Biopsy
samples of the formalin-fixed tissue were removed from regions shown on
the computer functional maps to represent reduced MIBG and
normal MIBG.
Sections 30 µm thick were cut from each sample and mounted on
gelatin-coated slides. For immunolocalization of tyrosine hydroxylase,
sections were washed in 0.1% Triton X-100 in 0.1 mol/L phosphate
buffer (pH 7.3) three times for 5 minutes each. The sections were then
covered with 50% normal serum for 30 to 60 minutes and drained. Each
section was incubated in antibody to tyrosine hydroxylase (Eugene Tech
International) at a dilution of 1:1500 in 0.1 mol/L phosphate buffer.
The incubation was carried out at 4°C for 
40 hours.
The sections were then washed in phosphate buffer/Triton X-100 three times for 5 minutes each and incubated in 3% hydrogen peroxide for 30 minutes. After another three washings in phosphate buffer/Triton X-100, the sections were incubated in the appropriate second antibody for 1 hour and washed three times in 0.1 mol/L phosphate buffer (pH 7.3) for 5 minutes each. Each section was then incubated in avidin-biotin complexes and developed with the peroxidase reaction with diaminobenzidine as chromogen according to standard methods. After three washings in tap water (5 minutes each), the sections were dried at 60°C for 1 hour, dehydrated in xylene for 1 hour, coverslipped with mounting medium, and examined under the light microscope.
Statistical Analysis
Results are expressed as mean±SD. Differences are considered
significant at a value of P<.05. The percent denervated
myocardium and QT intervals were compared between animals
with and without VT by unpaired t tests and ANOVA where
appropriate.
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Results |
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Sympathetic Innervation
All of the animals from the colony showed regions of reduced MIBG uptake relative to thallium uptake, consistent with scintigraphic evidence of denervation (Fig 1
). The
reduced MIBG relative to thallium is shown in the functional maps as
regions of yellow to green, whereas the region of normal MIBG uptake is
color coded red. Antibody to tyrosine hydroxylase localized abundant
neural tissue in sections of myocardium showing normal MIBG
uptake (Fig 2A), whereas sections from regions with
reduced MIBG uptake showed a striking paucity of sympathetic nerves
(Fig 2B), confirming denervation. There was a tendency for the
denervation to localize to the apical, anterior, septal, and lateral
regions of the left ventricle, as opposed to the posterior and basal
regions. The extent of regional denervation varied from 5.3% to 53.4%
of the myocardium (Table 1). The four
control dogs all showed a homogeneous distribution of MIBG
(Fig 3), as has been seen in mongrel dogs.9
Antibody to tyrosine hydroxylase localized abundant normal-appearing
nerves throughout all regions examined.
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Arrhythmia Characterization and QT Interval
Arrhythmia findings are shown in Table 2.
Dogs with >10 PVCs per hour or VT were considered affected. Six of the
11 animals from this colony showed evidence of VT on ambulatory ECG.
The remaining 5 animals showed <10 PVCs per hour and no VT. The 4
control animals showed rare PVCs in 1 animal and no VT. When the dogs
were grouped into those with (n=6) and those without (n=5) evidence of
VT on ambulatory ECG, there was a significant difference in the percent
of denervated myocardium. The group with VT showed
35±16.5% denervation, whereas the group without VT showed 12±5.6%
denervation (P<.02). The control dogs showed minimal
denervation (4±1.1%; P<.01 versus VT group,
P<.05 versus group without VT). There were no significant
differences in QT, QTc, or QT variability among affected,
unaffected, or control dogs (Table 3).
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Discussion |
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Major Findings
The major findings from this study include (1) functional and histological evidence of heterogeneous sympathetic innervation in this colony of dogs with spontaneous ventricular arrhythmia and (2) a significant difference in the extent of regional denervation between animals with and without VT.
MIBG Scintigraphy
We used [123I]MIBG to assess the function of
sympathetic nerve endings. It has been well established that MIBG is
taken up by sympathetic nerves in a manner similar to
norepinephrine but is not metabolized.9 11
Because MIBG is initially localized to neuronal and nonneuronal sites
in dog myocardium,12 we performed the imaging
studies 3 hours after injection. Localization at this time is primarily
in neuronal sites.12 Although there is a correlation
between tissue norepinephrine and MIBG localization, the
distribution of MIBG most closely depicts the distribution of
sympathetic neurons with functioning uptake mechanisms. The ability of
sympathetic nerve terminals to take up catecholamines is a
more sensitive index of nerve function and viability than are measures
of catecholamine content.13 Hence, the
assessment of MIBG uptake provides an accurate depiction of myocardial
sympathetic innervation and allows a unique characterization of acute
and chronic alterations in regional sympathetic nerve function.
The functional evidence of regional denervation on MIBG imaging in the dogs from this colony correlated with histological evidence of paucity of catecholaminergic neural tissue in the same region. Sympathetic nerves were not present in regions showing reduced MIBG uptake. These findings suggest a true structural denervation. The extent of denervation in these animals far exceeds that found in normal dogs.9 Previous studies in normal dogs have shown reduced MIBG localized to the apex, consistent with the 4% denervation seen in the control dogs in this study. Extensive involvement of the myocardium, as found in this colony of animals, has not been seen in normal dog hearts. The abnormalities in innervation are not inherent to the breed, because the control German shepherds all had homogeneous innervation. In addition, various conditions associated with regional abnormalities in MIBG uptake, such as infarction, diabetes, hypertrophic cardiomyopathy, and renal disease, were not identified in these animals.12 The distribution of MIBG uptake found in several of the dogs from this colony appears to be similar to the distributions that result from experimentally induced regional denervation, particularly right stellectomy.9
Sympathetic innervation of the developing dog heart can be demonstrated immunohistochemically from midgestation, increasing until about 2 months of age, when the adult pattern of neural tissue is achieved.10 Functional studies show an asymmetrical development of sympathetic innervation in newborn dogs as well.14 It is noteworthy that extensive areas of denervation were found in these German shepherd dogs at 6 months to 6 years of age, long after myocardial sympathetic nerves mature in the normal dog heart. Whether the regional absence of sympathetic nerves in these animals results from the failure of nerve ingrowth to specific regions of the heart (noninnervation) or to subsequent degeneration of previously intact nerves (denervation) cannot be determined from our data.
Heterogeneous Sympathetic Innervation and
Arrhythmogenesis
The sympathetic nervous system is known to play an important role
in the genesis of ventricular
arrhythmias.15 16 17 Catecholamines can
increase automaticity,18 induce triggered
activity,19 20 and create spatial dispersion of
refractoriness.21 Any of these conditions might serve as a
substrate for arrhythmias.
The majority of sudden deaths occur in patients with previous myocardial infarction and left ventricular dysfunction. The sympathetic nervous system may play an important role in post–myocardial infarction arrhythmia, possibly related to an acquired imbalance and heterogeneity of sympathetic innervation of the heart.22 Although the underlying mechanisms are poorly understood, a significant contributor to the increased risk of arrhythmia is thought to be a dispersion of repolarization.23 24 25 It has been shown in experimental studies that dispersion of repolarization can occur as a result of the dispersion of innervation after myocardial infarction, particularly during states of increased sympathetic tone.26 In addition, asymmetrical development of cardiac sympathetic nerves increases the vulnerability to ventricular fibrillation in newborn dogs and puppies.27
Numerous observations support an arrhythmogenic potential of dispersion of innervation, without myocardial infarction, in an otherwise structurally normal heart. Schwartz et al28 demonstrated that stimulation of the left stellate ganglion or removal of the right stellate ganglion lowered the ventricular fibrillation threshold. In contrast, removal of the left stellate ganglion raised the ventricular fibrillation threshold.28 29 Randall et al30 have demonstrated an increased incidence of spontaneous junctional and ventricular arrhythmias particularly during exercise after denervation of the heart sparing the ventrolateral cardiac nerve. These early studies led to the concept that heterogeneity of sympathetic innervation or "sympathetic imbalance" could adversely affect the electrical stability of the heart.31
Several recent clinical studies have shown regional heterogeneity of MIBG uptake in patients with VT and a "clinically normal heart."31 32 Gill et al33 showed that patients with VT had a greater extent of asymmetrical MIBG scans (47%) than subjects in the control group (0%). Of patients with exercise-induced VT and clinically normal hearts, 62% had asymmetrical MIBG scans with a tendency toward reduced MIBG uptake in the septum. In a study of patients with arrhythmogenic right ventricular cardiomyopathy, 40 of 48 patients showed regional reductions of MIBG uptake located primarily in the basal posteroseptal left ventricle.34 The left ventricles were otherwise structurally normal. All of the patients in the control group showed homogeneous innervation. Abnormalities in MIBG scintigraphy in patients with arrhythmogenic right ventricular cardiomyopathy correlated with the site of origin of VT, demonstrating regionally reduced uptake in 36 of 38 patients with right ventricular outflow tract tachycardia. The long-QT syndrome is another condition associated with ventricular arrhythmias in which abnormalities in regional MIBG uptake have been reported.35
In the long-QT syndrome, the hypothesis of an imbalance of cardiac sympathetic innervation creating the milieu for the life-threatening ventricular arrhythmias has lost favor with the recent genetic analysis defining ion channel dysfunction as the primary defect in many forms of the long-QT syndrome.36 However, the influence of a neurocardiac component in the long-QT syndrome has not been definitively ruled out. It is plausible that ion channel defects are the primary cardiac membrane abnormality in the long-QT syndrome but that sympathetic modulation is necessary for either triggering or perpetuating the ventricular arrhythmia. In the case of LQTS 2, the increase in action potential duration caused by the defect in the HERG gene may be augmented by catecholamines.36 37 Therefore, the dispersion of refractoriness created by the abnormality in potassium conductance may be increased by heterologous sympathetic innervation, thus decreasing the threshold for ventricular arrhythmias during sympathetic innervation.
The findings in this colony of German shepherd dogs with inherited
ventricular arrhythmias and sudden cardiac death
show some similarity to the clinical conditions mentioned above. The
evidence of regional denervation in otherwise structurally normal
hearts was striking. Previous studies have shown that the affected dogs
have a high incidence of frequent ventricular
arrhythmias with rapid episodes of polymorphic
VT.7 VT and PVCs are often pause dependent and occur more
frequently with sinus bradycardia. Occasional monomorphic VT is also
seen in the affected dogs. Dogs with frequent VT (10 runs/24 hours)
are more likely to die suddenly than those with less frequent VT. The
majority of sudden deaths occur during sleep or during rest after
exercise. All affected and unaffected dogs are robust and energetic,
without any ECG, echocardiographic, or pathological
evidence of structural or functional cardiac disease. These
observations suggest some influence of autonomic tone, possibly surges
in sympathetic nerve activity, on the pathogenesis of the
arrhythmia.
Although there was a significant difference in the extent of regional denervation between animals with and without VT in the present study, a cause-and-effect relationship cannot be established from these data. The frequency of the arrhythmia appears to be age related.38 The incidence and severity of ventricular arrhythmias increase between 7 and 28 weeks of age, with the peak incidence of arrhythmia corresponding to the peak incidence of sudden death. The overall incidence of arrhythmia decreases after 28 weeks of age in most but not all animals. Sudden death has been observed up to 120 weeks of age.7 Extensive denervation was found in two animals that were 6 years old, an age beyond the typical window of vulnerability for arrhythmia. One of these two animals continued to have increased ectopy until the time of study at 6 years of age, however. Further studies are needed to determine whether there is a mechanistic relationship between denervation and arrhythmia.
The arrhythmia in these animals has been shown to be inducible
with phenylephrine infusion, possibly resulting from the
combination of reflex bradycardia and direct stimulation of
-receptors.39 How these findings relate to regional
sympathetic denervation is unknown; however, it is possible that the
region of denervation may be supersensitive to
catecholamine stimulation. Purkinje fibers from affected
dogs have shown spontaneously occurring afterdepolarizations and
triggered activity that was enhanced by phenylephrine and
epinephrine.40 These fibers may arise from
denervated regions. The dispersion of sympathetic innervation may also
result in dispersion of repolarization, particularly during states of
increased sympathetic tone, such as REM sleep, thus providing the
substrate for propagation of the arrhythmia. The QT interval is
normal in these animals, which is not consistent with
dispersion of repolarization. However, abnormalities in repolarizing
currents (transient outward potassium current,
Ito) have been found in these
dogs.41 Whether these abnormal repolarizing currents are
spatially related to regions of sympathetic denervation is unknown.
The results reported here show that heterogeneous sympathetic innervation occurs in a colony of German shepherd dogs with inherited ventricular arrhythmia and sudden cardiac death. This naturally occurring model of sudden cardiac death provides unique opportunities to test long-standing hypotheses that relate sympathetic imbalance to arrhythmogenesis. Future studies to define the maturation patterns of myocardial sympathetic nerves, the effects of heterogeneous innervation on electrical stability, and underlying biochemical and genetic alterations may offer new insight into the enigma of sudden cardiac death in humans.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants HL-38105 (Dr Dae), HL-43821 (Dr Lee), and HD-23938 (Dr Moise) from the National Institutes of Health, Bethesda, Md. Computer applications support by Bill O'Connell and radiopharmaceutical support by John Huberty are gratefully acknowledged.
Received August 16, 1996; revision received February 17, 1997; accepted February 24, 1997.
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40. Gilmour R, Moise N. Triggered activity as a mechanism for inherited ventricular arrhythmias in German shepherd dogs. J Am Coll Cardiol. 1996;27:1526-1533.[Abstract]
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