(Circulation. 2000;101:516.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Evaluation of Sympathetic Nerve Terminals With [11C]Epinephrine and [11C]Hydroxyephedrine and Positron Emission Tomography
From the Division of Nuclear Medicine (O.M., P.C., D.M.W., M.S.), University of Michigan, Ann Arbor, Mich; and Department of Nuclear Medicine (G.M., N.T.B.N., S.N., S.Z., M.S.), Technische Universität München, Munich, Germany.
Correspondence to Markus Schwaiger, MD, Nuklearmedizinische Klinik, Klinikum Rechts der Isar, Ismaningerstr 22, Munich, Germany 81675.
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Abstract |
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Background—The goal of the present study was to directly compare the new radiopharmaceutical agent [11C]epinephrine (EPI) with [11C]hydroxyephedrine (HED) through the use of PET.
Methods and Results—Seven healthy volunteers and 10 patients were
investigated after heart transplantation. PET images of both tracers
were of excellent quality in the volunteers. Values for radiolabeled
metabolites (measured in percent of blood activity) at 5, 20, and 60
minutes after injection were 
35%, 82%, and 86% for EPI and
13%, 47%, and 78% for HED, respectively. At 35 minutes,
metabolite-corrected mean myocardial retention fraction of EPI
(0.235±0.022 min-1) was significantly greater
(P<0.01) than that of HED (0.142±0.012
min-1). Corrected tracer retention fractions of both EPI
and HED were significantly reduced in transplant recipients
(0.055±0.004 min-1, P<0.0001; and
0.050±0.006 min-1, P<0.0001,
respectively) compared with volunteers. Normalization of retention
fractions of patients with transplantation within 1 year to volunteers
resulted in a value (ratio expressed in percent) of 20.6±1.8%
for EPI, significantly (P<0.03) smaller than
27.8±0.8% for HED. In patients with transplantation later than 1
year, the values were 26.0±2.9% for EPI compared with 44.2±5.6% for
HED (P<0.014).
Conclusions—Both tracers showed high selectivity for neuronal uptake in the heart, with a significant reduction in tracer retention in transplant recipients compared with volunteers. Compared with HED, EPI showed greater retention in volunteers and a lower retention ratio in transplant recipients, suggesting that EPI may be the superior tracer with higher sensitivity to neuronal abnormalities. Because EPI reflects neuronal uptake, metabolism, and storage, it may be more suitable for the study of neuronal integrity than HED, which primarily traces uptake-1 capacity.
Key Words: tomography, emission-computed • heart transplantation • epinephrine • hydroxyephedrine
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Introduction |
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The importance of cardiac sympathetic nerve function under pathological conditions such as ischemic heart disease, cardiomyopathy, and heart transplantation is increasingly recognized.1 2 3 PET in combination with various tracers4 5 6 7 8 has been used for the noninvasive assessment of sympathetic nerve integrity. The best characterized PET tracer for presynaptic sympathetic nerve terminal assessment is [11C]hydroxyephedrine (HED).6 9 10 11 12 13 14 15 HED is a false neurotransmitter with the same neuronal uptake mechanism as norepinephrine, but it is resistant to degradation by monoamine oxidase and catechol-O-methyl-transferase.6 16 Studies that involved the isolated working rat heart model have shown selective HED uptake via neuronal uptake-110 ; however, the storage and release characteristics of HED appear to differ from those of the physiological neurotransmitters. Thus, HED is mainly suited for the assessment of uptake-1 function.11 Epinephrine (EPI) was developed as an alternative, more physiological tracer for the evaluation of presynaptic sympathetic nerve function with respect to uptake, vesicular storage, and metabolism.5 Studies in animals have shown that EPI is avidly transported into the presynaptic nerve terminal via uptake-1 and is stored in vesicles in a similar manner as norepinephrine.16
The purpose of the present study was to assess the suitability of EPI as an imaging agent for neuronal function in the human heart and to directly compare the myocardial kinetics of EPI with HED in the same patients. Studies were conducted in volunteers with no history of heart disease and in patients after heart transplantation.
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Methods |
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Subjects
Seven healthy volunteers served as controls. The absence of cardiac disease was established through history, physical examination, and resting ECG.
Ten patients who had undergone heart transplantation 3.5 to 48 months earlier were studied to evaluate tracer binding in global cardiac denervation early after transplantation and in regional denervation several years after surgery. Five patients had heart transplantation <1 year (group A) and 5 patients had transplantation >1 year (group B) before PET studies. Medications taken by transplant recipients included prednisone (5 to 12.5 mg QD), cyclosporin (Sandimmune; 125 to 225 mg BID), azathioprine (Imuran; 75 to 250 mg BID), and acyclovir (200 to 400 mg TID). Some patients were also taking nifedipine (Procardia) and furosemide (Lasix). No signs of transplant rejection were present at the time of the study. None of the patients were taking any medication, such as tricyclic antidepressants, that could interfere with norepinephrine uptake. All subjects provided written informed consent for participation in the study.
Radiosynthesis of [11C]HED and
[11C]EPI
HED was synthesized as previously described15
(specific activity >1000 Ci/mmol). Typical radiochemical and chemical
purities of the tracer for injection were 95% and 98%, respectively.
EPI was also synthesized as previously described5
(specific activity 900 to 2000 Ci/mmol). Radiochemical and chemical
purities were 98% and 97%, respectively.
Data Acquisition and Analysis
Subjects were studied with the use of a Siemens whole-body
scanner (ECAT 931, Siemens/CTI) with a germanium-68 ring source for
transmission scans as previously described.11 12 13 14 All
transplant recipients underwent both EPI and HED PET scanning; however,
1 of the 7 healthy volunteers did not have an HED-PET study performed
due to technical difficulties. EPI was injected
intravenously over 30 seconds, and simultaneous
PET image acquisition was initiated for 60 minutes. The scan sequence
consisted of 15 frames: 6x 30 seconds, 2x 60 seconds, 2x 150
seconds, 2x 300 seconds, 2x 600 seconds, and 1x 1200 seconds. After
1 hour to allow for 11C decay, the exact imaging
procedure was repeated with HED. ECG and blood pressure were monitored
before and immediately after injection.
To correct for the contribution of 11C-labeled metabolites in the blood activity, venous blood samples were drawn at 0, 1, 5, 10, 20, 40, and 60 minutes after the injections. The 11C-labeled metabolites from EPI were assayed with neutral alumina Sep-Pak cartridges (Waters). Sep-Pak cartridges were rinsed with double-distilled, deionized water; then, 1 mL of the blood sample was applied to a Sep-Pak cartridge with the use of a syringe, and the cartridge was rinsed with 3x 5 mL of 1.5 mol/L Tris-EDTA buffer (pH 8.6). Metabolites were eluded from the cartridge while the intact EPI was trapped. Similarly, the more polar 11C-labeled metabolites can be separated from intact HED with the use of a solid-phase extraction with C18 Sep-Pak (Waters) cartridges. Blood samples (1 mL) were deproteinized with acid and then adjusted to pH 6 to 7 with 2 mol/L KH2PO4. Each sample was centrifuged, and the supernatant was applied to an activated cartridge and rinsed with 3x 5 mL double-distilled and deionized water to elude labeled metabolites. The radioactivity in the eluents and in the cartridges was measured with the use of a gamma well counter. Relative concentrations of metabolites and intact tracers in blood were then calculated as a percentage of the total activity for each time point. Calculated fractions of intact tracers were plotted as a function of time. This curve was interpolated with the use of a cubic spline function, yielding intact tracer fraction at each time point in the blood time-activity curve generated from dynamic PET data. Metabolite correction was performed through the multiplication of the blood time-activity curve and the intact tracer fractions at the corresponding time points. The corrected blood time-activity curve was subsequently used as the arterial input function for the calculation of myocardial tracer retention.
A semiautomated volumetric sampling procedure was used to generate
tissue and blood time-activity curves, polar maps for analysis
of homogeneity of myocardial tracer distribution, and retention
fractions of tracers. After decay correction, retention fraction
(1/min) was calculated as:
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The clearance of tracers was defined from data between 10 to 60 minutes after injection that were fitted to a monoexponential function and expressed as half-time.
Data are shown as mean±SEM, except for patient and hemodynamic data, which were expressed as mean±SD. HED and EPI retentions from individual patients were compared with the use of a paired Student’s t test, and data for transplant recipients were compared with those for healthy volunteers with the use of an unpaired Student’s t test. P<0.05 was considered statistically significant.
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Results |
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Patient and Hemodynamic Data
The control group consisted of 7 male volunteers (mean age 32±5 years, mean weight 71.1±6.9 kg). The mean injected dose was 12.6±0.8 mCi for EPI and 20.4±1.3 mCi for HED. Hemodynamic data are summarized in Table 1
. These
subjects did not exhibit a hemodynamic response to
either EPI or HED.
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The transplanted group consisted of 10 patients (9 men and 1 woman,
mean age 51±8 years, mean weight 68.4±5.9 kg). The interval between
transplantation and PET imaging was 3.5 to 48 months. The mean injected
dose was 13.9±1.2 mCi for EPI and 20.7±0.7 mCi for HED. Transplanted
patients showed a significant increase in heart rate and in
systolic blood pressure after EPI injection (Table 1
).
Determination of 11C-Metabolites
Figure 1 illustrates the percentage
of total blood activity that is intact tracer at 0, 1, 5, 10, 20, 40,
and 60 minutes after injection of EPI and HED in volunteers and
transplant recipients. Metabolite assays were performed for each
patient except for 1 volunteer and 2 transplant recipients due to
technical difficulties. In these individuals, the mean values from the
pooled data of the respective group were used to correct the
arterial input function. There were no statistically
differences in the metabolite data between the transplant recipients
and with volunteers. As early as 5 minutes after tracer injection,
intact EPI was only 65% of total blood radioactivity. After 20
minutes, <20% was intact EPI, which decreased to 14% after 60
minutes. The appearance of metabolites in blood samples was delayed for
HED compared with EPI. Intact HED concentrations were 90% at 5
minutes, 50% at 20 minutes, and 25% at 60 minutes.
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Tracer Distribution
Examples of PET images are given for a volunteer (Figure 2) and for a patient 37 months after
transplantation (Figure 3). Both tracers
gave excellent image quality showing high myocardial uptake in healthy
volunteers and patterns of dramatically reduced uptake in transplant
recipients. The image displayed in Figure 3 also illustrates an
improvement in tracer accumulation in the anteroseptal region compared
with other regions of the heart in a patient with transplantation >1
year earlier. In patients with transplant within 1 year, a lack of
tracer accumulation in the myocardium was observed.
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To evaluate tracer distribution homogeneity, we analyzed tracer
retention in 5 myocardial regions (anterior, septal,
inferior, lateral, and apical); mean values are given in
Figure 4. Both tracers showed comparable
tracer distribution in the septal, anterior, and lateral walls. A
slight reduction was observed in the inferior wall and the
apex in healthy volunteers. The difference between the
inferior region and the anterior region was significant for
EPI but not for HED.
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Tracer Retention
Time-activity curves of tissue and blood for both HED and EPI in a
volunteer and a transplant recipient are illustrated in Figure 5. There was a rapid clearance of both
tracers from blood and a much slower clearance of activity from the
myocardium. As expected, the calculation of tracer
clearance from the myocardium resulted in a very long
clearance half-time (10 hours for EPI, 4 hours for HED; data are
given in Table 2). Although EPI showed a
trend toward a longer clearance half-time compared with HED, which is
consistent with the higher retention fraction of EPI compared
with HED, this difference was not statistically significant due to
large SDs. A decrease in tissue accumulation of both tracers was
observed in transplant recipients (up to 80% in denervated areas).
Similarly, clearance half-times of both tracers were significantly
shorter in transplant recipients than in volunteers. The clearance
half-time of EPI was also longer compared with that of HED in
transplant recipients.
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Myocardial retention fractions of both tracers were calculated with and
without metabolite correction. Retention fractions at 5, 15, and 35
minutes (representative of early, mid, and late time
points, respectively) are presented in Table 3. After metabolite correction, retention
fractions of both tracers in volunteers were significantly greater than
retention fractions without metabolite correction at all time points
(P<0.002).
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In a comparison of myocardial retentions of both tracers in volunteers,
EPI showed a higher retention than that for HED at all time points
(P<0.01). Linear regression analysis of retention
fractions for EPI versus HED revealed a significant correlation
(P<0.0001), as shown in Figure 6.
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, healthy volunteers.
In transplant recipients, the retention of both tracers was also
calculated with and without metabolite correction (Table 3). EPI
retention fractions in these patients were significantly lower than
that in volunteers (P<0.0001). Similarly, HED retention
fractions were significantly lower in transplant recipients than in
volunteers (P<0.0004). Patients with heart transplantation
were divided into 2 groups: group A (heart transplantation within
<1 year, n=5) and group B (heart transplantation >1 year earlier,
n=5). Although mean retention fractions over the entire
myocardium were not significantly different between the 2
groups, there was a significant increase in HED retention in the
anterior (P<0.03) and septal (P<0.03) regions
in group B compared with group A. An increase was also found in the
lateral wall (P<0.04), although it was not as visibly
apparent as in the anteroseptal regions. Although differences between
the 2 transplant groups in the retention fractions of EPI in the
anteroseptal walls did not reach statistical significance, there was an
apparent trend toward an increase in group B compared with group A.
To evaluate the specificity of the tracers, retention fractions
from whole myocardium and from the anterior wall of
transplant recipients were normalized to retention fractions of
volunteers, giving ratios of retention fractions expressed as a
percentage (Figure 7). The
transplant-to-normal ratios for EPI retention in group A, a model of
complete denervation (18.9±1.0%), was lower than the ratio in group B
(30.4±6.7%) in the anterior wall and in the entire
myocardium. However, this difference was not statistically
significant. Retention ratios for HED was significantly lower in group
A (29.1±1.9%) than in group B (62.6±11.6%), especially in the
anterior wall. In addition, transplant-to-normal ratios of HED were
significantly higher than those of EPI in group A, and the difference
was even greater in group B.
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Discussion |
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This study presents the application of 11C-labeled EPI as a new PET tracer for the noninvasive assessment of presynaptic sympathetic neuronal function in direct comparison with the previously developed tracer, HED. Similar to HED, EPI showed excellent myocardial uptake in healthy volunteers (Figure 2
) and significant reduction in tracer accumulation in
patients after heart transplantation (Figure 3).
The data showed a significant correlation between the retention
fraction of EPI and HED. Decay corrected time-activity curves of both
tracers (Figure 5) displayed high tissue retention with rapid
blood clearance. The results of metabolite analysis in blood
samples demonstrated the importance of the correction for
11C-metabolites to prevent underestimation of the
calculated myocardial retention of tracers.
Neither tracers showed the pharmacological effects in volunteers. EPI injection, however, caused a significant increase in heart rate and systolic blood pressure in transplant recipients. These hemodynamic alterations may be the consequence of a decrease in the clearance of EPI from the synaptic cleft due to a sympathetic presynaptic dysfunction or to a postsynaptic receptor supersensitivity in patients with heart transplants.17 18
Metabolite Correction
In contrast to HED, EPI is sensitive to neuronal
metabolism. Rapid degradation of EPI, producing
11C-metabolites in blood, may affect the
interpretation of kinetics data, because myocardial tracer retention
values are normalized to the integral of the arterial input
function. Thus, without the correction for metabolite activity in the
arterial input function, the calculated myocardial tracer
retention fractions are underestimated. Although HED is not susceptible
to neuronal metabolic degradation, it is metabolized by
liver tissue, producing 11C-metabolites (Figure 1), albeit much slower than EPI.
The nature of the assay used to detect metabolites in this study
does not identify the types of metabolites. It was designed to allow
fast clinical application, especially with the short half-life of
11C (20 minutes). For the purpose of correction
of the arterial function, however, it is only important to
determine the fraction of 11C-labeled metabolite.
It is not necessary to identify the metabolites themselves, assuming
that they are not substrates for neuronal uptake. In a study with HED
in rats, heart tissue was examined, and no significant metabolite
accumulation was detected.15 In another study, HPLC
analysis of rat heart 5 minutes after injection of EPI detected
16% of radioactivity in the form of metanephrine, a metabolite of
EPI. However, <2% was detected 30 minutes after
injection.16 Because metabolite concentrations detected in
blood samples were similar among transplant recipients and healthy
volunteers in this study, it is not possible to speculate on the
modulation in monoamine oxidase and
catechol-O-methyl-transferase activity in transplant
recipients compared with volunteers.
Tracer Homogeneity
It has been reported that myocardial tracer distribution of HED is
dependent on perfusion,11 but volunteers with no signs of
cardiac disease were assumed to have normal perfusion. Therefore, PET
perfusion studies were not performed. Nevertheless, data from healthy
volunteers showed homogeneous myocardial tracer
distribution with a slight reduction in accumulation in the
inferior and apical regions of the heart. These regional
differences in sympathetic innervation have also been described in
studies with the use of MIBG.19 20 21 22 23 The difference
in retention between the inferior wall and the anterior
wall was statistically significant for EPI but not for HED. SPECT
studies with MIBG, a marker for presynaptic sympathetic nerves, showed
heterogeneity in the sympathetic innervation in the
heart with significant reduction in uptake in the inferior
wall, especially in older male patients.23 It was
hypothesized that the sympathetic innervation in the
inferior wall may be reduced due to its predominate
parasympathetic innervation; therefore, EPI may be more sensitive than
HED in the detection of subtle changes in myocardial sympathetic
innervation. Further studies are necessary to determine whether age and
gender also affect the myocardial distribution of EPI.
Tracer Uptake and Storage
Evaluations of HED and EPI kinetics in the isolated rat heart
revealed selective neuronal uptake via neuronal uptake-1 in that
inhibition by desipramine (DMI) resulted in significant blockade of
tracer uptake of both tracers.10 16 The significantly
reduced tracer accumulation in patients who had recently undergone
heart transplantation confirms the selectivity of EPI and HED for
neuronal uptake. Moreover, the significant correlation between EPI and
HED retention fractions further illustrates the similarities between
EPI and HED as neuronal markers.
Despite similarities, retention fractions were higher with a longer clearance half-time for EPI than for HED in healthy subjects, suggesting a more efficient retention mechanism for EPI than for HED. Experimental findings in rats showed that the uptake of 3H-EPI was 4-fold higher compared with 3H-metaraminol, which is another catecholamine analog that is structurally similar to HED.24 One explanation for the higher uptake of EPI compared with its analog is a substrate preference for the physiological tracer, EPI.
Corticoids used as medication for immunomodulation in patients with heart transplantation may be inhibitors of uptake-2 (extraneuronal uptake).25 Thus, it has been suggested that the greater retention of EPI compared with HED in volunteers, which was not observed in transplant recipients, may reflect greater extraneuronal uptake of EPI in the normal heart. It has been shown that EPI has a greater capacity for extraneuronal uptake compared with norepinephrine in the isolated rat heart,26 but uptake-2 capacity may differ between animals and humans.20 Studies in isolated rat hearts showed that both EPI and HED exhibited a relatively small and limited amount of extraneuronal accumulation with DMI, which was reversible as demonstrated by the rapid clearance of both tracers with DMI.10 16
It is important to consider the role of extraneuronal uptake in the kinetics of the tracers, especially under various pathological conditions in which uptake-1 is altered. However, extraneuronal "uptake" is not likely to be the reason for the differences in tracer retention observed between EPI and HED, especially because extraneuronal "retention" is unlikely to contribute to the tracer retention at a late time point.
A major difference between EPI and HED is the neuronal retention mechanism. DeGrado et al10 demonstrated that HED can be displaced from the myocardium by DMI in the rat heart. These data suggest that HED is not avidly stored but instead undergoes continuous release and reuptake,10 because the highly lipophilic nature of the HED molecule may allow its passive diffusion across the neuronal plasma membrane. EPI was shown in the same experimental model to be more avidly retained by the myocardium and cannot be displaced by DMI,16 suggesting greater neuronal vesicular storage and better neuronal retention of EPI compared with HED. The dependency of myocardial retention of EPI on vesicular storage was confirmed with the use of the vesicular blocker reserpine. Pretreatment with reserpine showed inhibition of EPI retention by the heart. Although neuronal uptake of EPI is similar to the uptake of HED with respect to its high specificity for the uptake-1 carrier, EPI appears to be a marker for vesicular storage. Therefore, the dependency of HED retention on the reuptake process versus the stable vesicular storage of EPI is more likely the reason for the higher retention of EPI compared with HED in volunteers.
Tracer Retention in Transplanted Heart
The retention of both EPI and HED in the anteroseptal wall in
group A (<1 year transplantation) was lower compared with group B (>1
year transplantation), which is in concordance with previously
published data suggesting regional and partial recovery in the
transplanted heart.14 21 22 The significantly greater
retention of HED in the anterior wall of group B compared with group A
suggests a partial improvement in patients with earlier heart
transplantation. A recent longitudinal study by Bengel et
al,27 who used serial HED-PET studies to evaluate 20
patients (initial PET study at 0.2 to 12 years after heart
transplantation, follow-up study 2.4 to 4.2 years later), reported
evidence of a time-dependent, progressive reinnervation. EPI retention
fractions in the present study also showed an increasing trend in
group B compared with group A, but this increase was smaller than the
increase observed with HED. In addition, the transplant-to-normal
retention ratios of EPI were consistently smaller than those of
HED. This difference may indicate that EPI is more sensitive than HED
to sympathetic neuronal abnormalities. Furthermore, the difference in
the retention ratios between EPI and HED was even greater in group B
than in group A, showing a faster recovery in tracer accumulation of
HED compared with EPI. An explanation for this observation is a faster
improvement in uptake-1 function as shown with HED and a slower
recovery of neuronal vesicular storage capacity as reflected with the
use of EPI in the transplanted heart. However, this interpretation is
only speculative, and studies in a larger patient population are
necessary to delineate the integrity of the uptake-1 function and the
neuronal vesicular storage in the transplanted heart.
Conclusions
In this study, we presented the first clinical application
of the use of EPI as a PET tracer. The data showed that EPI is specific
for neuronal uptake. EPI exhibited high myocardial uptake with fast
blood clearance, similar to HED, providing excellent image quality.
Although both tracers showed comparable qualitative visualization of
sympathetic neuronal integrity, the mechanisms in the retention of EPI
and HED appear to differ. Neuronal uptake and retention of HED are
mediated by the uptake-1 function and a reuptake process. Although
neuronal uptake of EPI is also uptake-1 dependent, its retention is
dependent on vesicular storage and metabolism. EPI appears
to be a superior tracer compared with HED for the study of neuronal
integrity.
Received January 29, 1999; revision received August 19, 1999; accepted September 9, 1999.
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