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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

Michael W. Dae, MD; Randall J. Lee, MD, PhD; Philip C. Ursell, MD; Michael C. Chin, BA; Carol A. Stillson, BA; ; N. Sydney Moise, DVM

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

	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

	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.

	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.

	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.

View larger version (193K): [in this window] [in a new window]   Figure 1. Color functional map from dog S107. Large area of reduced MIBG uptake is indicated by yellow to green color. Red region represents normal MIBG uptake. Arrows show site of biopsy for immunohistochemical analysis (see Fig 2).

View larger version (104K): [in this window] [in a new window]   Figure 2. In a section taken from myocardium within red region (A), antibody to tyrosine hydroxylase localizes a nerve bundle (open arrow) and several individual nerve processes (thin arrows) coursing between ventricular muscle fibers. In myocardium from green region (B), same antibody discloses no neural tissue. Bar=50 µm.

View this table: [in this window] [in a new window]   Table 1. Summary of Age, ECG, and Imaging Results

View larger version (196K): [in this window] [in a new window]   Figure 3. Color functional map from control dog S214.

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, QT_c, or QT variability among affected, unaffected, or control dogs (Table 3).

View this table: [in this window] [in a new window]   Table 2. Arrhythmias in Dogs Based on 24-hour ECG Recording Made During Age of Peak Arrhythmia Expression

View this table: [in this window] [in a new window]   Table 3. QT Variables

	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, I_to) 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.

	Selected Abbreviations and Acronyms

 

MIBG = metaiodobenzylguanidine PVC = premature ventricular complex VT = ventricular tachycardia

	Acknowledgments

 
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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