Normal values and standardization of parameters in nuclear cardiology: Japanese Society of Nuclear Medicine working group database
Ann Nucl Med
Normal values and standardization of parameters in nuclear cardiology: Japanese Society of Nuclear Medicine working group database
Kenichi Nakajima 0 1 2 3 4 5
Naoya Matsumoto 0 1 2 3 4 5
Tokuo Kasai 0 1 2 3 4 5
Shinro Matsuo 0 1 2 3 4 5
Keisuke Kiso 0 1 2 3 4 5
Koichi Okuda 0 1 2 3 4 5
0 Department of Cardiology, Tokyo Medical University Hachioji Medical Center , Tokyo , Japan
1 Department of Cardiology, Nihon University Hospital , Tokyo , Japan
2 & Kenichi Nakajima
3 Department of Physics, Kanazawa Medical University , Uchinada, Ishikawa , Japan
4 Department of Radiology, National Cerebral and Cardiovascular Center , Suita , Japan
5 Emory University , Atlanta, GA , USA; Syntermed Inc. Atlanta , GA , USA Siemens Japan , Tokyo , Japan Nihon Medi-physics, Co. Ltd,, Tokyo, Japan Fujifilm RI Pharma, Tokyo, Co. Ltd, Japan University of Gothenburg , Gothenburg; EXINI Diagnostics, Lund , Sweden University of Michigan Health System; INVIA Medical Imaging Solutions, LLC , Ann Arbor, MI , USA
As a 2-year project of the Japanese Society of Nuclear Medicine working group activity, normal myocardial imaging databases were accumulated and summarized. Stress-rest with gated and non-gated image sets were accumulated for myocardial perfusion imaging and could be used for perfusion defect scoring and normal left ventricular (LV) function analysis. For single-photon emission computed tomography (SPECT) with multi-focal collimator design, databases of supine and prone positions and computed tomography (CT)-based attenuation correction were created. The CT-based correction provided similar perfusion patterns between genders. In phase analysis of gated myocardial perfusion SPECT, a new approach for analyzing dyssynchrony, normal ranges of parameters for phase bandwidth, standard deviation and entropy were determined in four software programs. Although the results were not interchangeable, dependency on gender, ejection fraction and volumes were common characteristics of these parameters. Standardization of 123IMIBG sympathetic imaging was performed regarding heart-to-mediastinum ratio (HMR) using a calibration
Japanese Society of Nuclear Medicine; (JSNM) working group; Normal database; Myocardial perfusion imaging; 123I-Metaiodobenzylguanidine (MIBG) quantification
Department of Nuclear Medicine, Kanazawa University
Hospital, 13-1 Takara-machi, Kanazawa 920-8641, Japan
phantom method. The HMRs from any collimator types
could be converted to the value with medium-energy
comparable collimators. Appropriate quantification based
on common normal databases and standard technology
could play a pivotal role for clinical practice and
In nuclear cardiology, providing reliable results is a basis
for clinical practice and research. Since nuclear cardiology
has been based on functional imaging, a number of
parameters have been calculated based on myocardial
perfusion imaging (MPI), metabolism and sympathetic
]. While normal values are important from a
physiological viewpoint, the values are influenced by
methodologies used for measurements of specific cardiac
parameters. Taking left ventricular (LV) ejection fraction
(EF) as an example, differences in the quantitative value
exist among echocardiography, left ventriculography with
contrast media, magnetic resonance imaging and X-ray
computed tomography (CT), and some differences have
been noticed even with nuclear imaging, including gated
blood-pool study and gated MPI using single-photon
emission computed tomography (SPECT) [
results also vary depending on the software used for
analysis, in which Quantitative Gated SPECT/Quantitative
Perfusion SPECT (QGS/QPS, Cedars Sinai Medical
Center, Los Angeles, CA, USA), Emory Cardiac Toolbox
(ECTb, Emory University/Syntermed Inc., Atlanta, GA,
USA), and 4DM-SPECT/Corridor 4DM (Michigan
University/INVIA, LLC, Ann Arbor, MI) are included [
]. In Japan, two software programs of Heart Function
View/Heart Score View (HFV/HSV, Nihon Medi-Physics
Co. Ltd., Tokyo, Japan) [
] and cardioREPO (FUJIFILM
RI Pharma, Co. Ltd., Tokyo, Japan/EXINI Diagnostics,
Lund, Sweden) have also been developed . When we
overview a variety of software programs, the threshold of
LVEF is critical not only for differentiation of normal
versus abnormal LV function, but also for prognostic
], since a large number of patients could be
included in the borderline range from 50 to 60%.
JSNM working group activities in 2007 and 2015
Both normal values and tracer distributions are important
in myocardial SPECT imaging. Patient-related factors,
such as sex and body habitus, may influence tracer
distribution. In addition, various technical factors may also be of
concern such as SPECT equipment, rotation range of
camera heads, collimator types, scatter and attenuation
corrections and crystal types, namely sodium iodide (NaI)
or cadmium zinc telluride (CZT) [
The Japanese Society of Nuclear Medicine (JSNM)
working group created SPECT databases for myocardial
perfusion imaging, fatty acid and sympathetic imaging, and
have provided normal files fitted for various software
programs (JSNM working group database 2007) [
The normal MPI studies were defined as subjects with low
likelihood of cardiac diseases with no evidences of the
following conditions: underlying known cardiac diseases,
electrocardiographic (ECG) evidence of ischemia or
infarction, wall motion abnormality, arrhythmia
inappropriate for gating and those with medications for
hypertension and diabetes. Both patients who had normal coronary
angiography and those who were not indicated for coronary
angiography because of a low possibility of coronary artery
disease were included. The MPI studies were performed
with a standard dose of 99mTc-methoxyisobutylisonitrile
(MIBI)/tetrofosmin (555-1110MBq) and 201Tl
In the working group database 2007, the databases were
separately created for rotation range (180/360 ), gender,
stress and rest, and radiopharmaceutical types including
123I-betamethyliodophenylpentadecanoic acid (BMIPP) and
123Imeta-iodobenzylguanidine (MIBG) (Table 1). The
collimator difference was only taken into considerations for
planar 123I-MIBG imaging. As a result of the working
group activity, normal databases applicable to conventional
non-attenuation corrected SPECT could be used in any
hospitals in Japan, and the initial multicenter validation
showed comparable diagnostic accuracy to expert reading
of MPI [
Subsequent working group activity of ‘‘Creation of
common databases in nuclear cardiology and
cross-calibration among software programs’’ began in October 2013,
and a 2-year project was conducted (Table 2). In the
current working group activity, data sets of gated and
nongated MPI were collected, and new SPECT databases of
201Tl and 99mTc-MIBI or tetrofosmin with multifocal
SPECT single-photon emission computed tomography, HMR heart-to-mediastinum ratio, LVEF left ventricular ejection fraction, LE low energy,
ME medium energy, LME low medium energy, US United States
collimation (IQ-SPECT, Siemens, Japan/USA) were added.
In the additional databases, both exercise and
pharmacological stresses were included, and well-controlled patients
with single medication for hypertension, dyslipidemia and
diabetes mellitus could be included. Normal values were
determined for each software program and applied to
clinical practice and works of research. Recently, although
new software of phase analysis has been developed [
normal values of the phase parameters have not been
presented in Japan. We therefore decided on all normal phase
dyssynchrony parameters including HFV and cardioREPO
software, which are commonly used in Japan. A project of
standardization of 123I- MIBG heart-to-mediastinum ratio
(HMR) was also performed using the calibration phantom
] as well as defect scoring based on a
17-segment polar map display [
Normal myocardial perfusion databases in the JSNM working group 2015
The characteristics of normal MPI databases are
summarized in Table 3 in the Japanese population including 201Tl
and 99mTc-perfufion tracers. Inclusion of 201Tl databases
Kanazawa University, Chief of the working group
Nihon University Hospital
Tokyo Medical University Hachioji Medical Center
National Cerebral and Cardiovascular Center
Tokyo Woman’s Medical University
Akita City Hospital
Tokyo Medical University
Kanazawa University Hospital
Kanazawa University School of Health Science
Kanazawa Medical University
Tokyo Woman’s Medical University
Fujita Health University Hospital
Sagamihara National Hospital
reflected the recent situations in Japanese nuclear medicine
practice. Recently in North America and Europe,
99mTcMIBI and tetrofosmin have been widely used, and the use
of 201Tl has been limited [
]. This has contributed to
reduced radiation exposure due to nuclear imaging, and
dual-isotope imaging has been discouraged. On the other
hand, in Japan, half of the MPI study has been performed
with 201Tl as of 2015. The background of this trend in
Japan is due to composite factors in favor of 201Tl, which
include better tracer extraction fraction, better defect
contrast, sufficient image quality even with a dose of
74–111 MBq, and single administration for both stress and
rest studies. However, 99mTc radiopharmaceuticals are
more appropriate for 16-frame gating, rather than 8-frame
gating, and have better physical characteristics for imaging.
Moreover, from the viewpoint of radiation exposure and
the possibility of stress-only study, when the study is very
], the use of 99mTc tracers will be increased
As another characteristics of Japanese database, both
360 and 180 rotation acquisition databases were
separately created. Although the 360 acquisition is still widely
used in Japan with multi-detector systems, most of the
N, mean ± SD, range
99mTc 206, 201Tl 79
cardiac studies are performed with a 180 acquisition in
North America and Europe. When Japanese MPI studies
with a 360 rotation acquisition were analyzed regarding
perfusion defect scores with QGS, the 360 rotation
acquisition database provided higher diagnostic accuracy
compared with databases from a 180 rotation acquisition
in the Japanese and American populations [
The normal perfusion databases are essential for
appropriate quantification of perfusion defects. Since
defect scores as summed stress/rest/difference scores (SSS/
SRS/SDS) depend on normal databases and software
algorithms, agreement among various software types is
considered desirable, but non-negligible difference in
scores does exit. Figure 1 shows a patient who showed a
mild to moderate degree of ischemia, when QGS, HSV and
cardioREPO are used for quantification. The scoring of
SSS ranged from 6 to 9, showing only minor differences.
Since the threshold of 10 % ischemia has been recognized
as the indication for coronary intervention when coronary
stenosis is [50 % [
], similar quantitative results at
least regarding this threshold are desirable, and further
comparative studies are required.
Myocardial perfusion database for short-time acquisition protocols
There are two possibilities for short-time acquisition
protocols, namely multifocal collimation with IQ-SPECT
(SMARTZOOM collimator; Siemens, Tokyo, Japan) and
CZT camera of either D-SPECT (Biosensors
Japan/Dynamic Spectrum, Israel; installed in 8 institutions as of
December 2015) or NM530c (GE healthcare, Japan;
installed in 8 institutions). This working group created
databases for IQ-SPECT, and the database for CZT camera
was investigated in another JSNM working group in 2014.
Compared with the Anger camera, the CZT camera
demonstrated dramatically higher performance, and the
IQSPECT system with special cardiac-dedicated collimation
also increased heart counts by focal magnification [
The CZT camera provided comparable diagnostic accuracy
as assessed by fractional flow reserve [
]. Combined use
of supine and prone imaging for detecting coronary artery
disease using the scoring method was effective for accurate
], and additional automatic quantification
based on standard databases is expected.
The IQ-SPECT system used multifocal collimators and
achieved 4 times higher counts in the heart compared with
the conventional parallel-hole collimator system [
]. With the collaboration of IQ-SPECT users, 201Tl
normal databases in supine and prone positions and
CTbased attenuation correction were created with scatter
correction and ordered subset conjugate gradient
minimization reconstruction . Additional 99mTc-MIBI/
tetrofosmin databases will be completed in 2016.
IQSPECT images show slightly different distribution of the
radiotracer due to its specific collimation (Fig. 2). The
prone position showed a higher count in the inferior walls
than the supine position, and gender difference was
observed. In contrast, CT-based attenuation correction
demonstrated more homogeneous distribution of each wall,
while the apical segment showed significantly decreased
activity in both genders. These observations are common
characteristics seen in attenuation-corrected SPECT
images with parallel-hole collimation [
]. The decreased
apical wall activity is partly due to the physiologically thin
apical wall and larger apical wall movement .
Although attenuation correction was considered potentially
useful and recommended [
], its use is still limited in
Japan, because nuclear medicine physicians and
cardiologists have become accustomed to using conventional
imaging without attenuation correction and inconsistency
of the effects of attenuation correction regarding camera
systems and processing tools [
]. However, since
stressonly imaging in combination with attenuation correction is
effective to appropriately identify low-risk patients [
], and true quantification in a unit of Bq/ml is a goal of
radioactivity measurement in SPECT, a CT-based
attenuation correction approach should be further pursued.
Normal values of LV function based on the updated gated SPECT databases
Normal values of LVEF and volumes were the basis for
evaluating cardiac function in various cardiac diseases [
]. According to the JSNM working group databases
(2007), EF was calculated higher for females than males
with QGS, and lower limits were approximately 50 % for
males and 55 % for female patients, which were slightly
higher compared with the study in the United States and
Fig. 2 IQ-SPECT normal databases created with supine and prone
positions, and CT-based attenuation correction (AC) and scatter
correction (SC). After CT-based correction, gender difference was not
Europe . The normal values at rest created by the
current JSNM database (2015) are shown using QGS
software in Tables 4 and 5. In small hearts, however,
underestimation of the true volume occurs and the effect is
higher for ESV than for EDV, resulting in an increase in
LVEF. This small-heart artifact is caused by the SPECT
reconstruction method optimized for blurred myocardial
walls. To minimize such artifacts, particularly in female
subjects and children, cardioREPO has adopted a corrected
algorithm for small hearts [
]. Average and standard
deviation (SD) calculated in 69 subjects are shown in
Fig. 3, focusing on the difference in software types.
Normal ranges of phase dyssynchrony parameters
Since four software programs are now available in Japan,
normal values of the phase parameters were compared.
Phase analysis has been used for more than 30 years using
a planar gated blood-pool study. Fourier transform was
applied to time-activity curves of each pixel, and phase and
amplitude of the fundamental frequency were displayed as
functional maps. The method was also used for gated
blood-pool SPECT, and three-dimensional propagation
patterns of phase were analyzed in patients with conduction
anomalies and ventricular asynergy [
the method was also applied to gated MPI, in which a
proportionate relationship between count and wall
thickness due to a partial volume effect was used for myocardial
time-activity curves [
]. Indications for cardiac
resynchronization therapy (CRT) might be one of the
promising applications [
]. Although a number of
parameters were proposed, most of the echocardiographic
parameters lack validation in appropriate clinical settings,
indicating striking variability, poor reproducibility, and
limited predictive power [
]. Whether a nuclear
approach provides robust results over ECG and LVEF
should be further investigated in patients who are indicated
When the same original data are provided, nuclear
medicine approach generally shows good reproducibility
or precision for LVEF and volumes and good correlation
to values derived from other modalities. In phase
parameters, however, normal values were still not
validated well. The working group activity therefore included
determination of normal values of phase parameters for
ECTb, QGS, HFV and cardioREPO (Fig. 4) [
on distribution of phase values in the LV, phase
histogram is created, and parameters of phase bandwidth, in
which 95 % of the phase distribution is included, phase
standard deviation (PSD) and phase entropy are
calculated. Phase entropy is an index of ‘‘disorder’’ defined by
Lower and upper limits were calculated by mean ± 2SD
All values are based on QGS software
EF ejection fraction, EDV end-diastolic volume, ESV end-systolic volume, EDVI EDV index, ESVI ESV index, PFR peak filling rate, MFR,
1/3MFR one-third mean filling rate, TPFR time to PFR, TPFR/RR, TPFR divided by RR interval
summation of [fi*log(fi)]/Log(n)], where f and n are
frequency in the i-th bin and number of bins, respectively,
which ranges from 0 to 1 (0–100%). When the normal
values were determined at rest based on the working
group database, the results could not be interchangeably
used. However, some similarities in normal ranges existed
between ECTb and cardioREPO and between QGS and
HFV, which probably depended on the computation
algorithm of each software program. The upper limit of
PSD was 20 for ECTb and cardioREPO, and 10 for
QGS and HFV. All software programs showed higher
PSD and bandwidth in male subjects than in female
subjects. In addition, the higher SD and bandwidth were
related to the larger LV volume and the lower EF, which
depended on software types. Finally, since the upper limit
of the normal values was not the best threshold for the
effective indication to CRT [
], the optimal threshold
should be separately validated.
Standardization of 123I-MIBG HMR for multicenter
123I-MIBG has a long history of clinical use in Japan since
1992, and major indications have been chronic heart failure
(CHF) and Lewy-body diseases [
application of MIBG in CHF, a number of studies in Japan,
Europe and the United States have unanimously shown that
low HMR and high washout rate (WR) were related to poor
outcomes including cardiac death, progression of heart
failure and occurrence of lethal arrhythmia [
multicenter studies and meta-analysis, the threshold of
HMR for poor prognosis was around 1.6–1.8. In contrast,
patients who showed HMR [2.0 showed good prognosis.
However, it has been understood that significant
differences in HMR exist among hospitals depending on
scinticameras and collimators [
20, 56, 57
]. In the JSNM working
group normal databases, while average late HMR with a
low-energy (LE) collimator was 2.5, that with a
mediumenergy (ME) collimator was 3.0 [
]. To obtain stable
results, the recommendation of European Association of
Nuclear Medicine Cardiovascular Committee and
European Council of Nuclear Cardiology was to use the
MEtype collimator [
]. However, in clinical practice a
number of hospitals continue to use the LE high-resolution
(HR) collimator in Europe and North America, and LE
general purpose (GP) or low-medium energy (LME) has
also been widely used in Japan.
To adjust the differences in camera-collimators, while
the multi-energy window acquisition method and direct
empirical correction method have been proposed, they
were not practical for applying the method to all possible
camera-collimator conditions. The calibration phantom
method was developed in Japan, which used specific
phantoms to obtain two HMRs from anterior and posterior
]. Based on the phantom experiments in each
institution, the conversion coefficient in each
camera-collimator system was determined, and all the HMRs could be
converted to the condition of the most common ME general
purpose (GP) collimator with a conversion coefficient of
] (Table 6). The linear regression equation among
the system used the formula passing on the coordinate of
HMR (1,1). It is based on the assumption that HMR should
be 1, when cardiac activity is equal to mediastinal activity.
The experiments have already been performed in 500
hospitals in Japan, and in more than 30 camera-collimator
conditions in Europe as of the end of 2015.
When the threshold HMR was converted to the
condition of the MEGP collimator, the threshold of
ADMIREHF (1.6, with LEHR), Sapporo Medical University (1.74,
with LEGP) and the pooled database in Japan (1.68, with
LE collimators in 6 hospitals) were converted to around 2.0
]. In a neurology field, the thresholds of differentiating
Alzheimer disease and dementia with Lewy bodies were
2.0–2.2 in a multicenter study in Japan [
effectiveness of standardization included not only diagnosis but
also prognostic evaluation. The mortality rate in the
Japanese pooled database was analyzed, and 2 and 5-year
mortality risk models were created [
]. In this
multivariate model, parameters of age, sex, LVEF, New York
Heart Association functional class, and late HMR were
used. In addition, since 123I-MIBG WR differs significantly
based on the use of background and decay correction and
timing of late imaging, standardization of methodology is
also required for calculating WR .
With the advent of the CZT camera, 123I-MIBG planar
image may not be a part of clinical routine study.
D-SPECT, however, provides a planogram comparable to
Table 6 Normal HMR after
(conversion coefficient = 0.88)
the planar anterior view [
]. Based on these reconstructed
planar images, HMR can be similarly calculated, although
the camera field of view is narrow. When HMRs from the
D-SPECT and the Anger camera were compared, a linear
relationship was obtained. Moreover, when the Anger
image HMR was standardized to HMR with the ME
condition as proposed, both D-SPECT and planar standardized
methods showed similar HMR values, indicating feasibility
of standardization in including planar and SPECT studies
123I-MIBG defect scoring using normal SPECT
The degree of segmental defect in 123I-MIBG SPECT can
be scored using a similar 17-segment model used for MPI.
Although visual scoring can be used, the distribution of
123IMIBG differs significantly in myocardial walls, showing
lower count particularly in the inferior region. Although
comparative scores between perfusion and 123I-MIBG have
been used [
], appropriate databases are particularly
important for 123I-MIBG imaging. The JSNM working
group created 123I-MIBG databases for the first time to
quantify defect scores and is clinically available now [
(Fig. 5). Moderate agreement could be observed between
HMR and defect scores. However, the problem of defect
scoring was in patients with a general decrease in the whole
heart, since the scoring implicitly assumes that normal
myocardial remains in some segments of the myocardium
. A new idea for scoring is necessary when HMR is very
low in a whole heart, which is sometimes seen in
Lewybody diseases and severe heart failure. At present, defect
scoring has a complimentary role for evaluating the severity
of three-dimensional 123I-MIBG defects.
Importance of normal database and future trends
Standardized viewpoints based on normal databases are
important for appropriate diagnosis in heart diseases. The
JSNM working group provided information on normal
control values and database sets as well on clinical works
and research. Recently, conventional SPECT systems have
been upgraded to SPECT-CT, which created different
Washout rate (decay and background corrected)
Average conversion coefficients were 0.55 for LEHR collimator, 0.65 for LEGP collimator, 0.65 or 0.75 for
extended LEGP collimator (depending on types), 0.83 for LMEGP collimator, 0.88 for MEGP collimator
and 0.95 for ME low penetration collimator [
HMR heart-to-mediastinum ratio, WR washout rate
distribution patterns by CT-based attenuation corrections.
In addition, solid-state cameras provide specific count
distributions in the myocardium in addition to high
resolution and sensitivity. Although we could not create all
possible normal databases in this working group activity,
common standard databases created by JSNM will
contribute to standard interpretation of nuclear images.
Moreover, since amount of ischemia is used for diagnostic
threshold for the indications of coronary intervention, it is
convenient if at least the diagnostic threshold determined
by different software shows similar defect scores.
Phase parameters were determined in JSNM working
group activity. However, it should be further investigated
whether a nuclear approach shows advantages over
conventional criteria using ECG and LVEF or
Regarding standardization of 123I-MIBG HMR,
conversion to MEGP-collimator comparable values is
occurring in Japanese hospitals. Various collimators including
LEHR, LEGP, extended LE, MEGP and ME low
penetration collimators are used at present in Japan. Although
the HMR is a simple parameter of planar count ratio of the
heart to background regions, it is important to consider that
a minor difference potentially creates significant
differences in prognosis. If correlation to SPECT methods and
planar HMR becomes clear, wider application of MIBG
can be anticipated using the standardized parameters. Since
we found good correlation between D-SEPCT and
standardized HMR using the Anger camera, creation of large
standardized databases would be feasible after
standardization. In future studies, clinical use of 123I-MIBG
imaging should incorporate individual patient risk stratification
and determine roles for therapeutic decision-making in
patients with CHF [
The JSNM working group of nuclear cardiology created
common normal databases fitted for conventional SPECT
system and SPECT-CT imaging with multifocal
collimators. While quantification by nuclear medicine software is
supported by the normal values, the values are not
interchangeable for any software types and the characteristics of
the calculated parameters should be kept in mind for
Acknowledgments This work was partly supported by the working
group activity of the Japanese Society of Nuclear Medicine and by
Grants-in-Aid for Scientific Research in Japan (PI: Kenichi
Nakajima). Emory Cardiac Toolbox was kindly supplied by Syntermed,
Inc. (Atlanta, GA, USA) and Corridor 4DM by INIVA Medical
Solutions, LLC (Ann Arbor, MI, USA). The Authors also thank Karin
Toth, MSc, for the batch processing of the data with cardioREPO, and
Mr. Yu Yamanaka (Kanazawa Medical University) for his help in
preparation of databases, and Mr. Ronald Belisle for editorial
assistance in the preparation of the manuscript.
Compliance with ethical standards
Conflict of interest KN has collaborative research with Fujifilm RI
Pharma Co., Ltd., which supplies 123I-MIBG in Japan and developed
software. KN also was involved in developing cardiac software with
Nihon Medi-Physics (Tokyo, Japan).
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