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Iodine-123 Metaiodobenzylguanidine Imaging and
Carbon-11 Hydroxyephedrine Positron Emission
Tomography Compared in Patients With Left
Ventricular Dysfunction
Ichiro Matsunari, MD, PhD; Hirofumi Aoki, MD; Yusuke Nomura, MD, PhD; Nozomi Takeda, RN;
Wei-Ping Chen, MD, PhD; Junichi Taki, MD, PhD; Kenichi Nakajima, MD, PhD;
Stephan G. Nekolla, PhD; Seigo Kinuya, MD, PhD; Kouji Kajinami, MD, PhD
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
Background—Although both 123I-metaiodobenzylguanidine (123I-MIBG) imaging and 11C-hydroxyephedrine (11C-HED)
positron emission tomography (PET) are used for assessing cardiac sympathetic innervation, their relationship remains
unknown. The aims were to determine whether 123I-MIBG parameters such as heart-to-mediastinum ratio (H/M) are
associated with quantitative measures by 11C-HED PET and to compare image quality, defect size, and location between
123
I-MIBG single-photon emission computed tomography (SPECT) and 11C-HED PET.
Methods and Results—Twenty-one patients (mean left ventricular ejection fraction, 39⫾15%) underwent 123I-MIBG
imaging and 11C-HED PET. Early (15-minute), late (3-hour) H/M, and washout rate (WR) were calculated for
123
I-MIBG. Myocardial retention and WR was calculated for 11C-HED. Using a polar map approach, defect was defined
as the area with relative activity ⬍60% of the maximum. Both the early (r⫽0.76) and late (r⫽0.84) 123I-MIBG H/M
were correlated with 11C-HED retention. 123I-MIBG WR was correlated with 11C-HED WR (r⫽0.57). Defect size could
not be measured in 3 patients because of poor quality 123I-MIBG SPECT, whereas 11C-HED defect was measurable in
all patients. Although defect size measured by early or late 123I-MIBG SPECT was closely correlated with that by
11
C-HED PET (early: r⫽0.94; late: r⫽0.88), the late 123I-MIBG overestimated defect size particularly in the inferior and
septal regions.
Conclusions—123I-MIBG H/M gives a reliable estimate of cardiac sympathetic innervation as measured by 11C-HED PET.
Furthermore, despite the close correlation in defect size, 11C-HED PET appears to be more suitable for assessing
regional abnormalities than does 123I-MIBG SPECT. (Circ Cardiovasc Imaging. 2010;3:595-603.)
Key Words: nervous system 䡲 sympathetic 䡲 radioisotopes 䡲 tomography
odine-123 metaiodobenzylguanidine (123I-MIBG, a norepinephrine analogue) imaging is known to provide important
clinical information on cardiac sympathetic neuronal function
in various cardiac disorders such as heart failure (HF),1
coronary heart disease (CHD),2,3 and arrhythmogenic heart
diseases.4 In particular, planar imaging– derived semiquantitative parameters of 123I-MIBG such as heart-to-mediastinum
uptake ratio (H/M) or myocardial washout rate (WR) are of
prognostic significance in HF patients, as demonstrated by a
number of studies.5–9 Furthermore, regional denervation,
which may be linked to ventricular arrhythmia,10 can be
assessed by single-photon emission computed tomography
(SPECT) imaging, although the low myocardial uptake of
123
I-MIBG, particularly in HF patients, may pose limitation
for accurate measurement of denervated area.
I
Clinical Perspective on p 603
Positron emission tomography (PET) using tracers for sympathetic innervation such as 11C-hydroxyephedrine (11C-HED)11–13 or
11
C-epinephrine14 is a more sophisticated imaging technique as
compared with 123I-MIBG imaging with higher sensitivity,
spatial resolution, and the possibility of absolute quantification
by routine use of attenuation/scatter correction.15 However, its
clinical experience is limited because it is methodologically
demanding, including the necessity for an on-site cyclotron.
Therefore, interpretation of 11C-HED PET is still a challenge
from the viewpoint of clinical significance because of the lack of
large clinical data. In this regard, it would be useful to know how
11
C-HED PET measurements are associated with those of more
widely available techniques such as 123I-MIBG imaging.
Received November 3, 2009; accepted May 27, 2010.
From The Medical and Pharmacological Research Center Foundation (I.M., N.T., W.-P.C.), Hakui, Japan; the Department of Cardiology (H.A., Y.N.,
K.K.), Kanazawa Medical University, Uchinada, Japan; the Department of Nuclear Medicine (J.T., K.N., S.K.), Kanazawa University Hospital,
Kanazawa, Japan; and the Department of Nuclear Medicine (S.G.N.), Technical University Munich, Munich, Germany.
Correspondence to Ichiro Matsunari, MD, The Medical and Pharmacological Research Center Foundation, Wo 32, Inoyama, Hakui, Ishikawa,
925-0613, Japan. E-mail matsunari@mprcf.or.jp
© 2010 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
595
DOI: 10.1161/CIRCIMAGING.109.920538
596
Circ Cardiovasc Imaging
September 2010
The purposes of this study were to determine whether
planar 123I-MIBG imaging– derived parameters such as H/M
or WR are associated with quantitative parameters measured
by 11C-HED PET, and to directly compare image quality,
defect size, and location between 123I-MIBG SPECT and
11
C-HED PET.
Methods
Study Population
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
This was a retrospective analysis of observational study to characterize HF using imaging biomarkers. Although the imaging protocol
included 11C-acetate PET to assess oxidative metabolism, this part
was not used in this study. 123I-MIBG imaging was performed when
it is clinically indicated by referring physician. We consecutively
screened 38 patients who had been referred to The Medical and
Pharmacological Research Center Foundation as potential candidates
of the study using the following criteria: (1) angiographically proven
CHD or nonischemic symptomatic HF, because both disease conditions are known to cause abnormalities in cardiac sympathetic
innervation,7,15 (2) regional or global (left ventricular ejection
fraction [LVEF] of ⬍50%) left ventricular (LV) dysfunction documented by echocardiography or ECG-gated myocardial perfusion
SPECT at entry, and (3) both 123I-MIBG imaging and 11C-HED PET
having been performed under stable general condition within 1
month after the entry. The first criterion was met in all 38 patients;
the second criterion was met in 31 patients. Of these, 21 patients met
the third criterion and thus were included in the study. Patients were
excluded if they (1) had decompensated HF, (2) had acute coronary
events (⬍10 days) such as myocardial infarction or unstable angina
before the imaging study, (3) had any cardiac event or clinical
instability requiring changes in medical treatment between the 2
imaging visits, or (4) were premenopausal women. All cardiac
medications such as ␤-blockers were continued during the study
period for safety reasons. All patients underwent 123I-MIBG imaging
and 11C-HED PET within a mean of 5.7 days (1 to 16 days). The
study protocol was approved by the institutional ethical committee
and written informed consent was obtained from all the participants
at the time of screening.
123
I-MIBG Imaging
Anterior planar imaging for 5 minutes was performed 15 minutes and
3 hours after intravenous injection of 111 MBq of 123I-MIBG using
a triple-head camera system (Prism 3000, Picker, Cleveland, Ohio)
equipped with low-energy parallel-hole collimators. Images were
acquired for 5 minutes using 512⫻512 matrices. After completion of
planar imaging, SPECT was acquired for 15 minutes in 64⫻64
matrices over 360° with an acquisition time of 30 seconds per
projection in 4° increments. An energy window centered on the
159⫾15.9 keV. The image data were reconstructed by use of a
standard filtered back-projection with a Butterworth filter (cutoff
frequency, 0.24; order 8). Neither attenuation nor scatter correction
was performed.
The H/M was measured for both early (15-minute) and late (3-hour)
images by placing the regions of interest on the entire LV myocardium
and upper mediastinum. Additionally, background and decay corrected
WR from the early to delayed images was calculated.6
Positron Emission Tomography
PET imaging was performed using a full-ring PET scanner (Advance, GE Healthcare). After positioning the subject in a supine
position in the gantry, transmission scan for 15 minutes was
performed using 68Ge/68Ga pin sources for attenuation correction.
After completion of transmission scan, 600 MBq of 11C-HED was
intravenously injected, and a dynamic imaging sequence (14 frames,
6⫻30, 2⫻60, 2⫻150, 2⫻300, and 2⫻600 seconds) was acquired.
Additionally, venous blood samples were drawn to measure plasma
norepinephrine (NE) and brain nautriuretic peptide (BNP) as the
neurohormonal markers of HF severity.
Attenuation-corrected transaxial images were reconstructed using
ordered subset expectation maximization algorithm. The image data
matrix was 128⫻128 with pixel sizes of 2.73 mm and a slice
thickness of 4.25 mm. Both attenuation and scatter corrections were
used during image reconstruction.
Processing of PET Data
A volumetric sampling procedure was used to create polar maps of
activity distribution throughout the entire LV myocardium. From the
dynamic PET images, global myocardial 11C-HED retention fraction
was calculated as the LV myocardial activity at the last frame (30 to
40 minutes) divided by the integral of the arterial blood activity
curve, which was derived from a small circular region of interest in
the left ventricular cavity. Additionally, 11C-HED WR was obtained
as the difference in activity between the early (10- to 15-minute) and
the late (30- to 40-minute) images divided by the early image.16
Comparison of 123I-MIBG SPECT and 11C-HED PET
For tomographic data, image quality was assessed by 2 readers. Each
SPECT or PET image data set was assigned good, fair, or poor
(suboptimal). The disagreements in image quality assignment was
resolved by consensus. The patients with poor image quality in at least
1 of the 3 image data sets (ie, early and late 123I-MIBG SPECT, and
11
C-HED PET) were excluded from further analysis because reliable
defect size quantification would not be possible in such patients.
Comparison of defect size and location between 123I-MIBG
SPECT and 11C-HED PET was performed using a semiquantitative
polar map approach, which was developed and validated at the
Technical University of Munich.17 The SPECT and PET images
were normalized to the mean of 6 connected sectors showing the
highest overall uptake in the LV myocardium. A pixel in the
patient’s map was considered abnormal if its count activity was
⬍60% of the maximum.18 The defect size was measured for the
apical, anterior, septal, lateral, and inferior regions and for the whole
LV, and was expressed as the percentage of LV myocardium (%LV).
Intraobserver and Interobserver Agreements
To test intraobserver agreement of defect size measurements, a single
reader analyzed both 123I-MIBG SPECT and 11C-HED PET twice in
every patient. To reduce recall bias, the second analysis was performed
at least 1 month after the first analysis. Additionally, the data were analyzed
independently by another reader to test interobserver agreement.
Echocardiography
Echocardiography was performed in all patients on the same day of
PET imaging using Vivid 7 (GE Healthcare) with a 4-MHz transducer. LVEF was measured using the Simpson biplane method.
Statistical Analysis
Data are expressed as mean⫾1SD. A paired t test was used for
comparison of hemodynamic variables between the 2 imaging visits.
Correlations of variables were analyzed by linear regression. The
defect size between 123I-MIBG SPECT and 11C-HED PET was
compared using repeated-measures ANOVA, followed by the Dunnett
multiple comparison test. For correlation analysis of imaging versus
neurohormonal parameters, the logarithmical transformation of BNP
was performed to normalize the distribution of its plasma concentration
because BNP is known to be rarely normally distributed.19,20 Intraobserver and interobserver agreements were assessed by intraclass correlation coefficient and Bland-Altman plots. Analysis was performed
using SPSS 18, JMP 8, or GraphPad Prism 5, where appropriate.
Results
Patient Characteristics
Patient characteristics are summarized in Table 1. There were
15 men and 6 women with a mean age of 66⫾8 years. In this
study, none of the 21 patients met the exclusion criteria and
had to be excluded from the study because they were in stable
66
47
76
60
64
66
56
78
68
60
67
67
59
69
58
61
75
76
81
70
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
F
Unknown
etiology
Unknown
etiology
Amyloid CM
Amyloid CM
Valvular
disease
Non-MI
Non-MI
Non-MI
MI
MI
MI
MI
MI
MI
MI
MI
MI
MI
MI
LCx
...
...
...
...
...
LCx
LAD
RCA
LCx
LAD
RCA
LAD
LAD
LAD
LAD
RCA
LAD
LAD
LAD
LAD
HT
HT
DM, HT
VF
DM
DM, HT, HL
DM
DM, Asthma
DM, HT
1
2
3
3
2
3
1
1
1
1
1
2
1
2
3
2
3
3
2
2
4
55
39 (14)
30
22
26
30
31
49
66
58
40
40
27
55
59
16
43
26
27
46
33
38
210
98.0
15.4
4253
174
84.2
133
24.9
10.0
16.4
72.6
235
230
54.5
359
150
67.8
748
529
53.4
132
121
455 (385) 360 (910)
471
1950
483
627
394
309
214
105
255
427
582
134
427
448
373
592
798
270
179
300
BNP,
pg/mL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5608 (1181)
5757
5749
5568
8464
8507
5120
4320
5670
4712
5040
6080
4667
6347
5180
5621
4520
4473
5743
6167
6240
3813
ACEI
␤Ca
Mean RPP
or ARB Blocker Digitalis Diuretic Nitrate Antagonist Spironolactone on 123I-MIBG
5677* (1224)
5893
5592
5058
7245
8836
5301
4640
5922
4629
4875
6058
4911
6880
4532
5544
5544
4444
5461
7553
6720
3583
Mean RPP
on 11C-HED
MI indicates CHD with prior myocardial infarction; non-MI, CHD without prior myocardial infarction; CM, cardiomyopathy; LCx, left circumflex artery; LAD, left ascending artery; RCA, right coronary artery; HT, hypertension;
DM, diabetes mellitus; HL, hyperlipidemia; VF, ventricular fibrillation; LVEF; left ventricular ejection fraction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and mean RPP, product of mean
blood pressure and heart rate.
*P⫽0.57 versus mean RPP on 123I-MIBG.
M
F
MI
MI
NE,
pg/mL
I-MIBG Imaging and
M
M
F
M
F
M
M
M
M
M
F
M
F
M
M
M
M
M
Diagnosis
123
Mean
(SD)
59
1
Age,
y
Sex
Infarct-Related
Artery in MI (or
NYHA
Stenosed Artery in Complicated Functional
Non-MI)
Diseases
Class
LVEF, %
Patient Characteristics
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Table 1.
Matsunari et al
11
C-Hydroxyephedrine PET
597
598
Circ Cardiovasc Imaging
September 2010
Figure 1. Scatterplots showing relationships
between the early 123I-MIBG H/M ratio and
11
C-HED retention (left), and between late 123IMIBG H/M ratio and 11C-HED retention (right).
Solid line indicates regression line.
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
general conditions. Sixteen patients had CHD (13 had a
history of myocardial infarction, and subsequent percutaneous coronary intervention on their infarct-related arteries) and
5 had nonischemic HF (1 valvular disease, 2 amyloid cardiomyopathy, and 2 HF of unknown underlying disease). The
mean LVEF as measured by echocardiography was 39⫾14%.
Functional status as assessed by New York Heart Association
functional class and medication regimens remained unchanged in all patients. Similarly, hemodynamic variables did
not differ significantly during the study period.
SPECT, the image quality was fair in all 21 patients. For the
late 123I-MIBG SPECT, the quality was fair in 18 patients and
was poor in 3 patients. These 3 patients with poor-quality late
123
I-MIBG images were considered to be suboptimal for
defect size quantification and were therefore excluded from
the further analysis, whereas 11C-HED defect was measurable
in all patients. The mean late H/M in this subgroup was
1.57⫾0.19, as compared with 1.90⫾0.29 (P⫽0.08) in the
remaining patients with acceptable image quality. An example of poor 123I-MIBG image quality is presented in Figure 2.
Planar 123I-MIBG Imaging Parameters and
11
C-HED PET
Intraobserver and Interobserver Reproducibility
Intraobserver and interobserver agreements were good for
both PET and SPECT, with intraclass correlation coefficients
of 0.98 to 0.99 for intraobserver and 0.95 to 0.99 for
interobserver agreement. Bland-Altman plots demonstrated
no evidence of systemic bias for both 123I-MIBG SPECT and
11
C-HED PET (Figure 3), although the limits of 2SDs of the
difference of 123I-MIBG SPECT tended to be wider as
compared with those of 11C-HED PET.
As illustrated in Figure 1, both the early and late 123I-MIBG
H/M were significantly correlated with 11C-HED retention.
Additionally, there was a significant correlation between
123
I-MIBG WR and 11C-HED WR (r⫽0.57, P⬍0.01).
The relationships between 123I-MIBG or 11C-HED parameters versus functional or neurohormonal measures of HF
severity are summarized in Table 2. LVEF was significantly
correlated with most of the image-derived parameters except
for early 123I-MIBG H/M. Plasma NE showed a close
correlation with 11C-HED WR (0.78) and a moderate correlation with 123I-MIBG WR (0.44) but did not with 123I-MIBG
H/M or 11C-HED retention. Additionally, 123I-MIBG H/M or
11
C-HED retention was negatively correlated with logarithm
of plasma BNP, whereas 123I-MIBG WR or 11C-HED WR
was positively correlated with it.
123
I-MIBG SPECT and
11
C-HED PET
Image Quality Assessment of Tomographic Data
By visual inspection, the quality of 11C-HED images was
judged as good in all 21 patients. For the early 123I-MIBG
Table 2. Correlation Coefficients: Matrix Between
11
C-HED Parameters and LVEF, Plasma NE, or BNP
Early
I-MIBG
H/M
123
LVEF
0.36
Late
I-MIBG
H/M
123
0.55*
123
I-MIBG
WR
⫺0.53*
123
11
C-HED
Retention
0.57*
I-MIBG or
11
C-HED
WR
⫺0.46*
NE
⫺0.27
⫺0.43
0.44*
⫺0.41
0.78*
Log BNP
⫺0.51*
⫺0.67*
0.61*
⫺0.58*
0.53*
Log BNP indicates logarithm of plasma BNP.
*Statistically significant correlation (P⬍0.05).
Comparison of Defect Size and Location Between
I-MIBG SPECT and 11C-HED PET
The relationships of defect size between 123I-MIBG SPECT
and 11C-HED PET are shown in Figure 4. The defect size
measured by either early or late 123I-MIBG SPECT was
closely correlated with that measured by 11C-HED PET.
Comparison of defect size between 123I-MIBG SPECT and
11
C-HED PET are summarized in Table 3. There was no
significant difference in total defect size between the early
123
I-MIBG SPECT and 11C-HED PET. The late 123I-MIBG
SPECT, on the other hand, showed a larger defect as compared
with 11C-HED PET. When the defect sizes were further analyzed according to their location, the inferior and septal regions
showed a larger late 123I-MIBG defect than 11C-HED. Conversely, the apex and anterior region showed a slightly smaller
123
I-MIBG defect than 11C-HED. Figure 5 illustrates a representative case example with a more extensive inferior defect with
123
I-MIBG SPECT than with 11C-HED PET.
123
Discussion
To the best of our knowledge, this is the first study that
compared 123I-MIBG imaging and 11C-HED PET in the same
individual patients. The major findings of this study were that
(1) 123I-MIBG H/M were significantly correlated with quan-
Matsunari et al
123
I-MIBG Imaging and
11
C-Hydroxyephedrine PET
599
Figure 2. 123I-MIBG SPECT and 11C-HED PET
images from a male patient with anterior myocardial infarction. The quality of early and late
123
I-MIBG SPECT and 11C-HED PET images
were judged as fair, poor, and good, respectively. In particular, the low myocardial tracer
uptake and intense adjacent liver activity on the
late 123I-MIBG SPECT degrades the image
quality. SA indicates short axis; VLA, vertical
long axis; and HLA, horizontal long axis.
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
titative measure of sympathetic innervation (ie, 11C-HED
retention) by PET, (2) cardiac 11C-HED WR was significantly correlated with 123I-MIBG WR and plasma NE level,
(3) 11C-HED PET consistently showed better image quality
than 123I-MIBG SPECT, and (4) late 123I-MIBG SPECT
overestimated the defect area particularly in the inferior and
septal regions as compared with 11C-HED PET.
123
I-MIBG and 11C-HED as Tracers for Assessing
Cardiac Sympathetic Innervation
123
I-MIBG and 11C-HED are currently the most established
single-photon and positron-emitting tracers for assessing
cardiac presynaptic sympathetic neuronal integrity.7,15 Both
tracers are analogs of NE, not metabolized, and thus marks
the location of functioning nerve terminals.11,21 Our prior
Figure 3. Bland-Altman plots and intraclass correlation coefficients with 95% confidence intervals in parentheses for 11C-HED PET and
123
I-MIBG SPECT defect size showing interobserver and intraobserver variabilities. Solid lines indicate mean difference; dotted lines,
limits of 2 SDs of the difference.
600
Circ Cardiovasc Imaging
September 2010
Figure 4. Scatterplots showing relationships of defect size between the early
123
I-MIBG SPECT and 11C-HED PET (left),
and between late 123I-MIBG SPECT and
11
C-HED PET (right). Solid line indicates
regression line.
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
experimental study using rabbit hearts has shown that both
tracers are highly specific for sympathetic neurons.16 From a
technical viewpoint, however, there are many differences
between planar imaging and PET. The former only gives
semiquantitative parameters such as H/M, whereas the later
provides truly quantitative measures of neuronal density.22
Despite this, 123I-MIBG H/M, particularly late H/M, were
well correlated with 11C-HED retention, supporting the concept that the simple semiquantitative H/M gives a reliable
estimate of cardiac sympathetic innervation.
In the present study, we measured plasma NE and BNP as
neurohormonal makers of HF severity because these markers
reflect different pathophysiologic aspects of HF. BNP is
released from the myocardium and its plasma level reflects
myocardial wall stress,19 whereas plasma NE is a marker of
systemic sympathetic nerve activation.23 Although plasma
NE is elevated only at a later stage of HF,24 both markers are
known to provide important prognostic information in HF
patients.19,23 It should also be noted that unlike the imaging
parameters tested in this study such as 123I-MIBG H/M and
11
C-HED retention, plasma NE is not specific for cardiac
sympathetic function. When the imaging parameters were
compared with functional or neurohormonal parameters,
11
C-HED retention showed a similar correlation pattern (ie,
significant correlations with LVEF and plasma BNP, but not
with NE) to late 123I-MIBG H/M, suggesting that 11C-HED
Table 3. Defect Size and Location Assessed by
SPECT and 11C-HED PET
Early
I-MIBG
123
Late
I-MIBG
123
11
123
C-HED
I-MIBG
P
Value*
Anterior
2.8⫾3.8
2.6⫾3.7†
4.1⫾5.1
0.036
Inferior
8.0⫾5.6
11.3⫾5.0†
6.2⫾6.6
⬍0.001
Septal
7.3⫾5.6
8.2⫾5.7†
5.9⫾6.6
0.008
Lateral
3.8⫾5.0
5.2⫾4.8
5.9⫾6.0
0.06
Apex
9.7⫾8.0†
12.7⫾7.0
11.7⫾8.0
0.003
Total
31.6⫾23.2
39.9⫾20.0†
33.8⫾25.4
0.004
Values are expressed as %LV (mean⫾SD).
*P values by repeated-measures ANOVA.
†P⬍0.05 versus 11C-HED.
retention and late 123I-MIBG H/M may reflect similar physiological aspects of HF. It is also notable that 11C-HED WR
was significantly correlated with plasma NE. To date, only
little attention has been given to 11C-HED WR in literature.
Besides the short physical half-life of 11C, a possible reason
for this is that 11C-HED binding to storage vesicles is
considered to be relatively low as compared with that of
NE.15 However, our prior experimental study in rabbit hearts
has shown that reserpine inhibitable fraction of 11C-HED is
greater than that of 123I-MIBG,16 suggesting that the former is
more specific for intravesicular uptake than the later. In this
regard, it is conceivable that 11C-HED WR may reflect
cardiac sympathetic nerve activity at least to some degree, as
does 123I-MIBG WR, although the clinical value of 11C-HED
WR remains to be elucidated by further studies. This is also
supported by the significant correlation between 11C-HED
WR and 123I-MIBG WR observed in this study.
Tomographic Imaging
There is a general agreement that the sympathetic nervous
system plays an important role in the genesis of ventricular
arrhythmias and an increased risk of sudden death.25 Recent
studies have shown that the regional variation of presynaptic
sympathetic function as assessed by SPECT10 or PET26 may
be linked to some forms of lethal ventricular arrhythmias.
However, image quality is a critical issue for reliable measurement of such regional abnormalities on tomographic data.
Our results demonstrated that 11C-HED PET consistently
showed better image quality than 123I-MIBG SPECT. More
importantly, a small but not negligible number of patients
(14%) showed poor-quality late 123I-MIBG images, where
measurement of regional abnormalities was not possible in a
reliable manner. The quality of 11C-HED PET images was
still good in all such patients, indicating that 11C-HED PET is
more suitable for assessment of regional abnormalities than
123
I-MIBG SPECT. In other words, regional analysis with
123
I-MIBG SPECT may be difficult when its image quality is
suboptimal. It is also important to note that image quality may
affect reproducibility of measurements, which is supported by
our data showing a trend toward lower variability with
11
C-HED PET than with 123I-MIBG SPECT. The better
Matsunari et al
123
I-MIBG Imaging and
11
C-Hydroxyephedrine PET
601
Figure 5. 123I-MIBG SPECT and 11C-HED PET
images from a male patient with amyloid cardiomyopathy. The late 123I-MIBG SPECT shows
a more extensive inferior defect as compared
with 11C-HED PET. SA indicates short axis;
VLA, vertical long axis; and HLA, horizontal
long axis.
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image quality of PET than SPECT is not surprising considering the technical advantages of PET over SPECT. Additionally, the lower injected dose of 123I-MIBG (111 MBq)
relative to that of 11C-HED (600 MBq) may have contributed
to the lower image quality. However, this reflects the standard 123I-MIBG imaging protocol practiced in Japan,6,9,27,28
where 111 MBq is the maximum dose limit for this tracer.
Furthermore, the intense adjacent liver uptake relative to the
myocardium, as illustrated in Figure 2, is not likely to be
improved by increasing the 123I-MIBG dose.
Despite the image quality differences described above, the
defect size measured by 123I-MIBG SPECT was closely
correlated with that measured by 11C-HED PET, indicating
that 123I-MIBG SPECT provides measures of regional sympathetic innervation if the image quality is acceptable. However, the late 123I-MIBG SPECT significantly overestimated
defect area as compared with 11C-HED PET, particularly in
the inferior and septal regions. In addition to possible differences in tracer kinetics between 123I-MIBG and 11C-HED,16
attenuation artifacts may certainly have contributed to the
results. Inferior and septal regions are known to be susceptible to
attenuation artifacts, which is particularly true in patients with
dilated LV such as those encountered in HF.29 Furthermore,
intense liver activity may have further lessened the inferior
myocardial activity during image reconstruction.30
Limitations
There are limitations of the study to be described. First, the
most significant limitation of the study is the lack of attenuation correction for 123I-MIBG SPECT, which would have
had a significant impact on SPECT image quality and would
make a proper comparison of the 2 tracers difficult. Additionally, relatively low spatial resolution of current SPECT system
limits the clear delineation of myocardium from the liver, which
may be further enhanced after correction. Perhaps for this
reason, attenuation correction for cardiac 123I-MIBG SPECT has
not yet been used in any of published data. Nevertheless, we
believe that further instrumental work should be directed toward
implementation of attenuation correction together with improved
spatial resolution and counting sensitivity. This would improve
SPECT image quality and enable more accurate 123I-MIBG
SPECT measurements, which may be possible using newer
generation cameras.31
Second, both PET and SPECT images were normalized to
the maximum of LV myocardium and a simple 60% threshold
was used to define defect area, which abolishes any difference in global tracer retention because the maximum is
always set to 100%. This is unavoidable with 123I-MIBG due
to the nonquantitative nature of SPECT. A true regional
defect versus normal will thus be underestimated in case of
overall downregulation of innervation that includes remote
myocardium. Thus, if PET is used and regional absolute
retention is compared with normal, defect size will be more
accurately assessed. We could not cover this issue in the
present study because we did not include normal data bases
for comparison.
Third, we relied on 11C-HED retention/washout as PET
measures of presynaptic sympathetic function because they
are simple and stable. More sophisticated compartment kinetic models have also been used for 11C-HED.32,33 Although
they are technically more demanding, the model based
quantitative parameters such as volume of distribution33 (Vd)
may be more specific to presynaptic uptake-1 function than is
11
C-HED retention. The comparative clinical significance of
these 11C-HED parameters remains to be investigated in
further studies. Furthermore, we assessed only presynaptic
neuronal function in the current study. The combination of
presynaptic and postsynaptic functions using PET has been
reported in patients with arrhythmogenic heart diseases33,34
and HF,35 which would provide more comprehensive understanding of underlying pathophysiology.
Fourth, plasma BNP, NE, and LVEF were measured on the
day of 11C-HED PET, and therefore it is possible that these
measurements would have been more favorably correlated
with 11C-HED results than with 123I-MIBG. Although the
both imaging procedures were performed under stable clini-
602
Circ Cardiovasc Imaging
September 2010
cal conditions with relatively short intervals (mean 5.7 days),
this possibility cannot be ruled out.
Fifth, the study patients were heterogeneous in underlying
etiology, including ischemic and nonischemic cardiac diseases. However, it has been shown that sympathetic neuronal
imaging reflects the disease severity independent of underlying cause,1 which was true in the current study as demonstrated by the relationship between imaging parameters and
functional or neurohormonal markers of HF. Finally, outcome data were not obtained in this study and therefore
comparative prognostic value of 123I-MIBG imaging and
11
C-HED PET is unknown.
9.
10.
11.
12.
Conclusion
123
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Semiquantitative I-MIBG H/M gives a reliable estimate of
cardiac sympathetic innervation as measured by 11C-HED
PET. Additionally, 11C-HED WR may serve as an index of
cardiac sympathetic neuronal activity, as does 123I-MIBG
WR, although this must be validated in further studies. As for
tomographic imaging, although there is a close correlation in
measured defect size between SPECT and PET, the late
123
I-MIBG SPECT overestimates defect size particularly in
the inferior and septal regions. More importantly, 11C-HED
PET consistently yields better quality images and appears to
be more suitable for assessing regional abnormalities than
123
I-MIBG SPECT. In other words, regional analysis with
123
I-MIBG SPECT may be difficult when its image quality is
suboptimal.
Sources of Funding
This work was supported by Ishikawa prefectural government.
Disclosures
13.
14.
15.
16.
17.
18.
19.
None.
References
1. Imamura Y, Ando H, Mitsuoka W, Egashira S, Masaki H, Ashihara T,
Fukuyama T. Iodine-123 metaiodobenzylguanidine images reflect intense
myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause. J Am Coll Cardiol. 1995;26:1594 –1599.
2. Bengel FM, Barthel P, Matsunari I, Schmidt G, Schwaiger M. Kinetics of
123I-MIBG after acute myocardial infarction and reperfusion therapy.
J Nucl Med. 1999;40:904 –910.
3. Matsunari I, Schricke U, Bengel FM, Haase HU, Barthel P, Schmidt G,
Nekolla SG, Schoemig A, Schwaiger M. Extent of cardiac sympathetic
neuronal damage is determined by the area of ischemia in patients with
acute coronary syndromes. Circulation. 2000;101:2579 –2585.
4. Agostini D, Scanu P, Loiselet P, Babatasi G, Darlas Y, Grollier G, Potier
JC, Bouvard G. Iodine-123-metaiodobenzylguanidine SPECT of regional
cardiac adrenergic denervation in Brugada syndrome. J Nucl Med. 1998;
39:1129 –1132.
5. Merlet P, Valette H, Dubois-Rande JL, Moyse D, Duboc D, Dove P,
Bourguignon MH, Benvenuti C, Duval AM, Agostini D, Loisance D,
Castaigne A, Syrota A. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med. 1992;33:
471– 477.
6. Imamura Y, Fukuyama T. Prognostic value of myocardial MIBG scintigraphy findings in patients with cardiomyopathy: importance of background correction for quantification of MIBG activity. Ann Nucl Med.
2002;16:387–393.
7. Yamashina S, Yamazaki J. Neuronal imaging using SPECT. Eur J Nucl
Med Mol Imaging. 2007;34(Suppl 1):S62–S73.
8. Agostini D, Verberne HJ, Burchert W, Knuuti J, Povinec P, Sambuceti G,
Unlu M, Estorch M, Banerjee G, Jacobson AF. I-123-mIBG myocardial
imaging for assessment of risk for a major cardiac event in heart failure
20.
21.
22.
23.
24.
25.
26.
27.
patients: insights from a retrospective European multicenter study. Eur
J Nucl Med Mol Imaging. 2008;35:535–546.
Kasama S, Toyama T, Sumino H, Nakazawa M, Matsumoto N, Sato Y,
Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M.
Prognostic value of serial cardiac 123I-MIBG imaging in patients with
stabilized chronic heart failure and reduced left ventricular ejection
fraction. J Nucl Med. 2008;49:907–914.
Bax J, Kraft O, Buxton A, Fjeld J, Pařı⬘zek P, Agnostini D, Knuuti J,
Flotats A, Arrighi J, Muxi A, Alibelli M, Banerjee G, Jacobson A.
123
I-mIBG scintigraphy to predict inducibility of ventricular arrhythmias
on cardiac electrophysiology testing: a prospective multicenter pilot
study. Circ Cardiovasc Imaging. 2008;1:131–140.
Schwaiger M, Kalff V, Rosenspire K, Haka MS, Molina E, Hutchins GD,
Deeb M, Wolfe E Jr, Wieland DM. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography.
Circulation. 1990;82:457– 464.
Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger
M. Effect of sympathetic reinnervation on cardiac performance after heart
transplantation. N Engl J Med. 2001;345:731–738.
Di Carli MF, Tobes MC, Mangner T, Levine AB, Muzik O, Chakroborty
P, Levine TB. Effects of cardiac sympathetic innervation on coronary
blood flow. N Engl J Med. 1997;336:1208 –1215.
Munch G, Nguyen NT, Nekolla S, Ziegler S, Muzik O, Chakraborty P,
Wieland DM, Schwaiger M. Evaluation of sympathetic nerve terminals
with [(11)C]epinephrine and [(11)C]hydroxyephedrine and positron
emission tomography. Circulation. 2000;101:516 –523.
Lautamaki R, Tipre D, Bengel FM. Cardiac sympathetic neuronal
imaging using PET. Eur J Nucl Med Mol Imaging. 2007;34 Suppl 1:
S74 –S85.
Nomura Y, Matsunari I, Takamatsu H, Murakami Y, Matsuya T, Taki J,
Nakajima K, Nekolla SG, Chen WP, Kajinami K. Quantitation of cardiac
sympathetic innervation in rabbits using 11C-hydroxyephedrine PET:
relation to 123I-MIBG uptake. Eur J Nucl Med Mol Imaging. 2006;33:
871– 878.
Nekolla SG, Miethaner C, Nguyen N, Ziegler SI, Schwaiger M. Reproducibility of polar map generation and assessment of defect severity and
extent assessment in myocardial perfusion imaging using positron
emission tomography. Eur J Nucl Med. 1998;25:1313–1321.
O’Connor MK, Gibbons RJ, Juni JE, O’Keefe J Jr, Ali A. Quantitative
myocardial SPECT for infarct sizing: feasibility of a multicenter trial
evaluated using a cardiac phantom. J Nucl Med. 1995;36:1130 –1136.
Yamamoto K, Burnett JC Jr, Jougasaki M, Nishimura RA, Bailey KR,
Saito Y, Nakao K, Redfield MM. Superiority of brain natriuretic peptide
as a hormonal marker of ventricular systolic and diastolic dysfunction and
ventricular hypertrophy. Hypertension. 1996;28:988 –994.
Kyuma M, Nakata T, Hashimoto A, Nagao K, Sasao H, Takahashi T,
Tsuchihashi K, Shimamoto K. Incremental prognostic implications of
brain natriuretic peptide, cardiac sympathetic nerve innervation, and noncardiac disorders in patients with heart failure. J Nucl Med. 2004;45:
155–163.
Wieland DM, Brown LE, Rogers WL, Worthington KC, Wu JL,
Clinthorne NH, Otto CA, Swanson DP, Beierwaltes WH. Myocardial
imaging with a radioiodinated norepinephrine storage analog. J Nucl
Med. 1981;22:22–31.
Ungerer M, Hartmann F, Karoglan M, Chlistalla A, Ziegler S, Richardt G,
Overbeck M, Meisner H, Schomig A, Schwaiger M. Regional in vivo and
in vitro characterization of autonomic innervation in cardiomyopathic
human heart. Circulation. 1998;97:174 –180.
Cohn JN. Abnormalities of peripheral sympathetic nervous system
control in congestive heart failure. Circulation. 1990;82:I59 –I67.
Minami M, Yasuda H, Yamazaki N, Kojima S, Nishijima H, Matsumura
N, Togashi H, Koike Y, Saito H. Plasma norepinephrine concentration
and plasma dopamine-beta-hydroxylase activity in patients with congestive heart failure. Circulation. 1983;67:1324 –1329.
Zipes DP. Influence of myocardial ischemia and infarction on autonomic
innervation of heart. Circulation. 1990;82:1095–1105.
Sasano T, Abraham MR, Chang KC, Ashikaga H, Mills KJ, Holt DP,
Hilton J, Nekolla SG, Dong J, Lardo AC, Halperin H, Dannals RF,
Marban E, Bengel FM. Abnormal sympathetic innervation of viable
myocardium and the substrate of ventricular tachycardia after myocardial
infarction. J Am Coll Cardiol. 2008;51:2266 –2275.
Tamaki S, Yamada T, Okuyama Y, Morita T, Sanada S, Tsukamoto Y,
Masuda M, Okuda K, Iwasaki Y, Yasui T, Hori M, Fukunami M. Cardiac
iodine-123 metaiodobenzylguanidine imaging predicts sudden cardiac
death independently of left ventricular ejection fraction in patients with
Matsunari et al
28.
29.
30.
31.
123
chronic heart failure and left ventricular systolic dysfunction: results from
a comparative study with signal-averaged electrocardiogram, heart rate
variability, and QT dispersion. J Am Coll Cardiol. 2009;53:426 – 435.
Toyama T, Hoshizaki H, Yoshimura Y, Kasama S, Isobe N, Adachi H,
Oshima S, Taniguchi K. Combined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, function, and
sympathetic nerve activity in patients with dilated cardiomyopathy: comparison with carvedilol therapy alone. J Nucl Cardiol. 2008;15:57– 64.
Matsunari I, Boning G, Ziegler SI, Nekolla SG, Stollfuss JC, Kosa I,
Ficaro EP, Schwaiger M. Attenuation-corrected 99mTc-tetrofosmin
single-photon emission computed tomography in the detection of
viable myocardium: comparison with positron emission tomography
using 18F-fluorodeoxyglucose. J Am Coll Cardiol. 1998;32:927–935.
Matsunari I, Tanishima Y, Taki J, Ono K, Nishide H, Fujino S, Matoba
M, Ichiyanagi K, Tonami N. Early and delayed technetium-99mtetrofosmin myocardial SPECT compared in normal volunteers. J Nucl
Med. 1996;37:1622–1626.
Herzog BA, Buechel RR, Katz R, Brueckner M, Husmann L, Burger IA,
Pazhenkottil AP, Valenta I, Gaemperli O, Treyer V, Kaufmann PA.
I-MIBG Imaging and
32.
33.
34.
35.
11
C-Hydroxyephedrine PET
603
Nuclear myocardial perfusion imaging with a cadmium-zinc-telluride
detector technique: optimized protocol for scan time reduction. J Nucl
Med. 2010;51:46 –51.
Caldwell JH, Kroll K, Li Z, Seymour K, Link JM, Krohn KA. Quantitation of presynaptic cardiac sympathetic function with carbon-11-metahydroxyephedrine. J Nucl Med. 1998;39:1327–1334.
Schafers M, Lerch H, Wichter T, Rhodes CG, Lammertsma AA,
Borggrefe M, Hermansen F, Schober O, Breithardt G, Camici PG.
Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol. 1998;32:181–186.
Wichter T, Schafers M, Rhodes CG, Borggrefe M, Lerch H, Lammertsma
AA, Hermansen F, Schober O, Breithardt G, Camici PG. Abnormalities
of cardiac sympathetic innervation in arrhythmogenic right ventricular
cardiomyopathy : quantitative assessment of presynaptic norepinephrine
reuptake and postsynaptic beta-adrenergic receptor density with positron
emission tomography. Circulation. 2000;101:1552–1558.
Caldwell JH, Link JM, Levy WC, Poole JE, Stratton JR. Evidence for preto postsynaptic mismatch of the cardiac sympathetic nervous system in
ischemic congestive heart failure. J Nucl Med. 2008;49:234 –241.
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
CLINICAL PERSPECTIVE
Iodine-123 metaiodobenzylguanidine (123I-MIBG) imaging provides information on cardiac sympathetic neuronal
function, which may be clinically useful in a variety of conditions including diabetes and heart failure. This study was
performed to determine whether semiquantitative 123I-MIBG parameters such as heart-to-mediastinum ratio (H/M) are
associated with quantitative measures of cardiac sympathetic innervation by 11C-hydroxyephedrine (11C-HED) positron
emission tomography (PET) and to compare image quality, defect size, and location between 123I-MIBG single-photon
emission computed tomography (SPECT) and 11C-HED PET in patients with regional or global left ventricular dysfunction
(mean left ventricular ejection fraction, 39⫾15%). We found that both the early (r⫽0.764) and late (r⫽0.844) 123I-MIBG
H/M were correlated well with 11C-HED retention. Myocardial 123I-MIBG washout rate was also correlated with 11C-HED
washout rate (r⫽0.569). For tomographic imaging, however, 123I-MIBG defect size could not be measured in 3 patients
because of poor SPECT image quality, whereas 11C-HED defect was measurable in all patients. Furthermore, although
defect size measured by early or late 123I-MIBG SPECT was significantly correlated with that by 11C-HED PET, the late
123
I-MIBG overestimated defect size particularly in the inferior and septal regions. Thus, 123I-MIBG H/M gives a reliable
estimate of cardiac sympathetic innervation as measured by 11C-HED PET. However, regional analysis with 123I-MIBG
SPECT may be difficult when its image quality is suboptimal.
Iodine-123 Metaiodobenzylguanidine Imaging and Carbon-11 Hydroxyephedrine Positron
Emission Tomography Compared in Patients With Left Ventricular Dysfunction
Ichiro Matsunari, Hirofumi Aoki, Yusuke Nomura, Nozomi Takeda, Wei-Ping Chen, Junichi
Taki, Kenichi Nakajima, Stephan G. Nekolla, Seigo Kinuya and Kouji Kajinami
Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017
Circ Cardiovasc Imaging. 2010;3:595-603; originally published online June 9, 2010;
doi: 10.1161/CIRCIMAGING.109.920538
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