ORIGINAL ARTICLE

Approach to establishment of a standard index for regionalwashout of a myocardial perfusion agent

Ryo Tanaka • Katuhiko Simada

Received: 18 May 2010 / Accepted: 9 August 2010 / Published online: 11 September 2010

� The Japanese Society of Nuclear Medicine 2010

Abstract

Objective Enhanced washout of 99mTc-SESTAMIBI

(MIBI) is found in the myocardium in patients after acute

myocardial infarction (AMI) or in those with serious

angina. However, a standard index for washout evaluation

in ischemic heart disease has not been established. We

approached the establishment of a standard index for

regional washout in ischemic heart disease and report the

evaluation results of a newly developed washout evaluation

method.

Methods We made a polar map from short-axis myocar-

dial SPECT images and developed a washout index (WO

INDx) based on early and delayed images. The control

group consisted of 10 healthy volunteers and a patient

group of 43 patients with AMI or angina. Three nuclear

cardiology specialists interpreted early and delayed images

and visually graded the regional uptake of MIBI in 17

segments on a polar map, and the washout rate (WR) was

compared with WO INDx.

Results WO INDx and WR in the control group were

1.83 ± 1.95 and 35.59 ± 6.97, respectively. In the AMI

cases the correlation of ejection fraction (EF) and WO

INDx was -0.602, and the correlation of EF and WR was

-0.346. The agreement between observers in the visual

evaluation was high with excellent to moderate agree-

ments. The ROC analysis was performed for WS2 with a

washout score of 2 in the visual evaluation by Observers

1 to 3. The area under the ROC curve (AUC) was 0.934,

0.949 and 0.934 for WO INDx, respectively, and 0.681,

0.662 and 0.656 for WR, respectively, indicating that the

AUC was higher for WO INDx. The sensitivity for WO

INDx was 89.3, 88.9 and 96.3%, respectively, and the

specificity was 88.2, 89.8 and 79.3%, respectively. The

sensitivity for WR was 53.6, 52.8 and 51.9%, respectively,

and the specificity was 87.5, 79.4 and 87.4%, respectively.

These results suggested that WO INDx had higher reli-

ability than WR in terms of sensitivity.

Conclusions The results suggested that the diagnosis

using a new index, WO INDx, calculated from standard-

ized percentage uptakes is more useful than that using the

washout rate determined from the myocardial count in the

MIBI washout evaluation.

Keywords 99mTc-Sestamibi � Washout � Standard index

Introduction

99mTc-sestamibi (MIBI), a myocardial perfusion agent, is

distributed along the blood flow and taken up by myocar-

dial cells. Most of the MIBI is not washed out and is

retained in mitochondria. Myocardial perfusion images

represent the MIBI distribution [1, 2].

However, it has been reported that in the myocardial

perfusion imaging after reperfusion in patients with acute

myocardial infarction (AMI), the delayed SPECT image

tends to have reverse redistribution which is the result of

enhanced washout of MIBI in regions exposed to ische-

mia for a certain period, as compared with normal regions

[3–6].

The significance of enhanced washout of MIBI, as

related to prognosis or therapeutic decision-making in

R. Tanaka (&)

Department of Radiology, Kushiro Sanjikai Hospital,

4-30 Nusamai-Cho, Kushiro, Hokkaido 085-0836, Japan

e-mail: hem2299@aol.com

K. Simada

Graduate School of Natural Sciences, Nagoya City University,

Nagoya, Japan

123

Ann Nucl Med (2010) 24:713–719

DOI 10.1007/s12149-010-0416-4

patients after treatment for AMI or those with serious

angina has been recognized.

However, the interval of early or delayed image

acquisition, the visual evaluation criteria and the calcu-

lation method for washout rate (WR) are not standardized

in institutions, and the washout evaluation method is still

debated. In the evaluation method for myocardial wash-

out, WR is generally determined with the following

equation: WR = {(early image - delayed image)/(early

image)} 9 100% [7]. WR using a planar image may be

an effective index when the washout is determined in the

whole myocardium in patients with myocardial disease

[8]. However, since the washout of MIBI is increased

only in a region that is subject to a coronary artery

occlusion in patients with ischemic heart disease associ-

ated with a coronary stenosis, it is difficult to evaluate the

washout using WR in the whole myocardium. Therefore,

the method for assessing washout of MIBI by visual

evaluation using short-axis, horizontal long-axis and ver-

tical long-axis slice images after reconstruction is adopted

in patients with ischemic heart disease associated with a

coronary stenosis [9]. In a different method, a polar map

for short-axis images is used to prepare a coronary artery

dominance map based on the myocardial maximum

counts from the apex to the basal area, and a region with

decreased tracer accumulation is regarded as an abnormal

region in comparison with a normal area with enhanced

washout [10].

However, a standard index for washout evaluation in

ischemic heart disease has not been established. The

establishment of such an index will significantly contribute

to the diagnosis in nuclear cardiology and reduce variation

in the diagnosis among institutions. We developed and

evaluated a new washout evaluation method for the

establishment of a standard index for regional washout in

myocardial ischemia and report the results here.

Materials and methods

Subjects

The control group consisted of 10 healthy volunteers (3

men and 7 women; mean age 37 ± 8 years) without a

previous history of chest pain or any abnormal findings on

ECG, chest X-ray or blood tests. The patient group con-

sisted of 43 patients (31 men and 12 women; mean age

64 ± 13 years). The number with AMI and angina (AP)

were 34 and 9, respectively. The numbers of patients with

AMI in right coronary artery (RCA), left anterior

descending coronary artery (LAD) and left circumflex

coronary artery (LCX) were 16, 11 and 7, respectively.

(1 vessel disease: 16, 2 vessel disease: 13 and 3 vessel

disease: 5). The numbers of patients with AP in RCA, LAD

and LCX were 4, 4 and 1, respectively (1 vessel disease: 8,

2 vessel disease: 0, 3 vessel disease: 1). Before the

examinations, the study was approved by the Institutional

Review Board. We explained the exposure level of MIBI to

healthy volunteers and patients, obtained written informed

consent with full understanding of our study based on the

ethic rules, and carried out the study.

Collection of SPECT images

A SPECT image obtained 1 h after injection of MIBI was

used as an early image with ECG gating. A SPECT image

acquired 6 h after injection of MIBI was used as a delayed

image [11]. Myocardial SPECT images were obtained

using a dual detector gamma camera (E-CAM, Toshiba

Medical Systems Corp.) equipped with a low-medium-

energy general purpose (LMEGP) collimator with an

energy window of 141 keV ± 10% and a 64 9 64 matrix.

Images were acquired over 360�, at 6� every 30 s and 60

projections were collected. SPECT images were recon-

structed with filtered back projection using a ramp filter.

A Butterworth filter was used in the preprocessing step, and

attenuation or scatter correction was not performed. Early

and delayed images were acquired under the same

conditions.

Visual score

Three nuclear cardiology specialists (Observers 1, 2 and 3)

interpreted early and delayed images and visually evalu-

ated the regional uptake of MIBI in 17 segments on a polar

map using the defect score (DS) on a 5-point scale: normal

perfusion, mild reduction in counts-not definitely abnor-

mal, moderate reduction in counts-definitely abnormal,

severe reduction in counts and absent uptake [12]. DS in

each segment was calculated from the score on early image

(early score) and the score on delayed image (delayed

score). The weighted kappa test was used to evaluate the

agreement rate between the observers.

Determination index

The washout score (WS) was calculated from early and

delayed scores obtained in the visual evaluation using (1).

WS was rated on a 4-grade evaluation: 0 (WS0), 1 (WS1),

2 (WS2) and 3 or higher (WS3). Considering variation in

the visual evaluation, WS of 2 points or higher was defined

as abnormal washout in this study and was compared with

the quantitative indices.

WS ¼ Delayed scoreð Þ � Early scoreð Þ ð1Þ

where WS = 0 when WS is negative.

714 Ann Nucl Med (2010) 24:713–719

123

Quantitative indices

In the quantitative evaluation, a polar map was made from

short-axis myocardial SPECT images and divided into 17

segments. Based on data obtained from the 17-segment

polar map, the washout rate (WR) and the washout index

(WO INDx) were calculated from early and delayed ima-

ges. WR was calculated from the mean count in each

segment on early or delayed images using (2). WO INDx

was calculated from the percentage uptake (%uptake) in

each segment on early and delayed images using (3).

Decay correction was performed for delayed images with

the physical half-time. Although the %uptake in each

segment on the polar map is generally a relative value that

is determined from the mean pixel value in each segment

with a maximum pixel value of 100%, %uptake in each

segment on the polar map was restandardized with a

maximum %uptake of 100% in the calculation of WO

INDx.

WR ¼ Early image count � Delayed image count

Early image count

� 100 ð2Þ

WO INDx

¼Early image %uptake

Early image MAX%uptake� 100

� �� Delayed image%uptake

Delayed imageMAX%uptake� 100

� �

Early image %uptake

Early image MAX%uptake� 100

� � � 100

ð3Þ

Results

Control data

In the control group, the mean WR (±S.D.) was

35.59 ± 6.97, and the maximum and minimum values were

47.6 and 25.3, respectively. The mean WO INDx (±S.D.)

was 1.83 ± 1.95, and the maximum and minimum values

were 6.6 and 0, respectively. In %uptake in early images of

the control group, no abnormal region with %uptake of 60%

or lower was observed. No abnormal region with %uptake of

60% or lower was observed in delayed images either.

Although there was a difference in %uptake between early

and delayed images in normal myocardium, no abnormal

myocardial perfusion was observed.

Data for ischemic heart lesions

The mean WR (±S.D.) in ischemic lesions was

36.52 ± 10.68, and the maximum and minimum values

were 66.9 and 9.7, respectively. The mean WO INDx

(±S.D.) was 6.05 ± 7.53, and the maximum and minimum

values were 44.1 and 0, respectively.

We investigated cardiac function and the relation

between WO INDx and WR in the AMI patients in whom

reperfusion treatment was successful. The average period

from PCI operation to SPECT imaging was 10.6 ±

7.6 days. The correlation of cardiac function and extent

score of WO INDx was ejection fraction (EF) in c =

-0.602 (p \ 0.001), end diastolic volume (EDV) in

c = 0.381 (p \ 0.05), end systolic volume (ESV) in

c = 0.374 (p \ 0.05), respectively, with these values all

significant. WR was EF in c = -0.346 (p \ 0.05), EDV in

c = 0.249 (ns), ESV in c = 0.302 (ns), respectively, and

significance was found in only EF.

Agreement for visual evaluation

As for the early score, the agreement was good between

Observers 1 and 2 with the weighted kappa (95% confi-

dence interval [CI]) of 0.716 (0.6630–0.7690), good

between Observers 1 and 3 with 0.7743 (0.7375–0.8110)

and moderate between Observers 2 and 3 with 0.5754

(0.5141–0.6368). As for the delayed score, the agreement

was good between Observers 1 and 2 with 0.8080

(0.7772–0.8388), excellent between Observers 1 and 3 with

0.8254 (0.8259–0.8790), and good between Observers 2

and 3 with 0.7571 (0.7218–0.7924) (Table 1).

Receiver operating characteristic (ROC) analysis

Table 2 shows the results of ROC analysis of quantitative

indices for WS2 in 3 observers. The areas under the ROC

curve (Area Under Curve: AUC) in Observers 1, 2 and 3

were 0.934, 0.949 and 0.934 for WO INDx, respectively, and

0.681, 0.662 and 0.656 for WR, respectively, indicating

higher AUCs for WO INDx. The cutoff values in Observers

1, 2 and 3 were 13.51, 13.75 and 9.90 for WO INDx,

respectively, and 23.2, 26.6 and 23.2 for WO INDx,

respectively, showing that WO INDx was able to more

Table 1 Agreement between the score on the early image and the score on the delayed score in the visual evaluation

Weighted kappa (95% CI) Observer 1 vs. Observer 2 Observer l vs. Observer 3 Observer 2 vs. Observer 3

Early score 0.7160 (0.6630–0.7690) 0.7743 (0.7375–0.8110) 0.5754 (0.5141–0.6368)

Delayed score 0.8080 (0.7772–0.8388) 0.8254 (0.8259–0.8790) 0.7571 (0.7218–0.7924)

High agreements were found between observers

Ann Nucl Med (2010) 24:713–719 715

123

clearly distinguish the stratified classification of visual

evaluation.

Sensitivity and specificity of quantitative indices

The sensitivity and specificity of WO INDx and WR for

WS2 in Observers 1, 2 and 3 were assessed. As for WO

INDx, the sensitivity (95%CI) was 89.3% (77.2–100.0%),

88.9% (74.3–100.0%) and 96.3 (88.4–100.0%), respec-

tively, and the specificity was 88.2% (84.0–92.4%), 89.8%

(85.9–93.6%) and 79.3% (73.7–84.9%), respectively. As

for WR, the sensitivity (95%CI) was 53.6% (19.9–87.2%),

52.8% (16.9–88.7%) and 51.9% (14.4–89.3%), respec-

tively, and the specificity was 87.5% (80.3–94.6%), 79.4%

(69.9–89.2%) and 87.4% (80.2–94.5%), respectively. WO

INDx had higher reliability than WR in terms of specific-

ity. The 95% CI was calculated using the variance in view

of correlation among 17 segments in each subject (cluster

structure) [13].

In addition, potential differences in the sensitivity and

specificity were tested between WO INDx and WR. Dif-

ferences in the sensitivity between WO INDx and WR

were 0.357 (p = 0.024), 0.361 (p = 0.024) and 0.444

(p = 0.034) in Observers 1 to 3, and significant differences

were found in 3 observers. Differences in the specificity

between WO INDx and WR were 0.007 (p = 0.862), 0.104

(p = 0.062) and -0.081 (p = 0.097) in Observers 1 to 3,

and no significant difference was seen in any observer

(Table 3). The tests for differences in the sensitivity and

specificity and the calculation of CI on difference were

performed using the method in view of correlation among

17 segments in each subject (cluster structure) [14].

Case report

A woman aged 69 years was urgently transported to hos-

pital because of AMI. Since 100% stenosis was found in

segment 7 of the left coronary artery, percutaneous

coronary intervention (PCI) was performed and the stenosis

rate was improved to 0%. The early myocardial perfusion

image after 1 week showed slightly reduced accumulation

in the apex as well as the apical anterior to antero-lateral

regions. The delayed image showed decreased accumula-

tion due to enhanced washout, which corresponded to the

infarct-related coronary artery. In the visual evaluation,

abnormal washout was found in 7 regions. When the

washout was determined from the mean cutoff value for

WS2 in the WO INDx evaluation, abnormal washout was

found in 7 abnormal regions which corresponded to the

regions in the visual evaluation. However, when the

abnormal washout was determined from the mean cutoff

values for WR, abnormal washout was found in all regions,

which did not correspond to the regions in the visual

evaluation (Fig. 1).

Discussion

After uptake into the myocardium along blood flow, most

MIBI is not washed out and remains in the myocardium [1,

2]. With such characteristics, we can identify ischemic

regions before PCI reperfusion in patients with myocardial

infarction. However, enhanced washout was observed in

the subacute phase after reperfusion and a perfusion defect

region on a delayed image could correspond to an ischemic

region before reperfusion. It has been reported that the

recovery of heart function varies depending on the size of

the perfusion defect region on delayed images [7]. In this

study, the WO INDx and the EF showed a stronger cor-

relation than that with WR. If the extent of abnormal WO

INDx increased, reduction of the cardiac function was

suggested, and it was thought to be more clinically useful

than WR. Since a perfusion defect region changes with

time during the subacute phase, it is important to determine

the most suitable timing of image acquisition as well as the

interval of acquisition [10]. In addition, accurate determi-

nation of enhanced washout is needed to correctly evaluate

the prognosis of the myocardium. In this study, we tried to

establish a standard index for enhanced regional washout in

patients with ischemic heart disease and evaluated the

index.

Washout of MIBI is generally calculated from the

counts in collected images or reconstructed images. How-

ever, there are differences in WR evaluation for the normal

region among individuals and a variation in the values for

WR is found. Therefore, a mismatch between WR and

visual evaluation is found in some patients. The compari-

son of WO INDx with WR in the control group indicated

that there was a greater variation in the values for WR

among individuals than in those for WO INDx. It is diffi-

cult to determine a standard index value when the value

Table 2 Results of ROC analysis of the quantitative indexes for WS2

in 3 observers

Observer AUC Sensitivity (%) Specificity (%)

WO INDx

1 0.934 89.30 88.20

2 0.949 88.90 89.80

3 0.934 96.30 79.30

WR

1 0.681 53.60 87.50

2 0.662 52.80 79.40

3 0.656 51.90 87.40

Comparison of WO INDx with WR using AUC, sensitivity and

specificity. AUC was higher for WO INDx than WR

716 Ann Nucl Med (2010) 24:713–719

123

varies widely among individuals. WR has high unevenness

due to individual differences in clinical cases of AMI, and

a discrimination value of abnormal WR cannot be deter-

mined. In this study, we could obtain data without variation

in the evaluation using the standard index for washout that

we developed. Standardization was performed using

%uptake on each polar map of early and delayed images as

an independent variable and realized a decreased difference

among individuals.

The visual evaluation is generally performed with a

maximum count of 100% in a normal region of the myo-

cardium. SPECT quantification is suitable for assessing the

regional uptake and can objectively evaluate the uptake

because a polar map is displayed with relative values (%) to

a maximum count. However, visual semi-quantitative

scoring in each segment decreases the objectivity because of

individual variation. Therefore, it would be appropriate that

the mean value of scores evaluated by three observers or

more is used in the visual semi-quantitative scoring [5, 12].

Information recognized by the eye is unclear in part, and

subjective information is not always consistent with

objective information in all persons. The value varies in

repeated measurements even when made by the same

observer. The signal detection theory [15] is used to purely

measure the sensitivity of the sensory system. Goodenough

et al. [16] applied the signal detection theory to their study

on image assessment and indicated that it was useful for

image assessment. In ROC analysis, the variation among

observers is generally small as compared with the visual

evaluation method, and an ROC curve is analyzed to

evaluate the lesion delectability and the diagnostic per-

formance [17, 18]. Since this study was performed based

on visual evaluation, we assessed the agreement of data

evaluated by three nuclear cardiology specialists and con-

firmed high agreement.

When an ROC curve was used to compare the quanti-

tative indices for WS2 in the visual evaluation, the sensi-

tivity was higher in WO INDx than WR, indicating that

WO INDx had superior sensitivity. When the visual eval-

uation was used as the standard, a newly developed index

(WO INDx) was found to have higher diagnostic perfor-

mance than the conventional index (WR). In other words,

WO INDx provides a perceptual effect that is closer to the

visual evaluation and shows a higher sensitivity of the

sensory system.

Myocardial washout in diffuse cardiac disease is con-

ventionally determined from the myocardial count on a

planar image [19, 20]. However, since in patients with

ischemic heart disease, washout is enhanced in an injured

region of the myocardium as compared with a normal

region, it is difficult to distinguish normal cells from

abnormal cells in the washout evaluation for the whole

myocardium. When an abnormal region with enhanced

myocardial washout is small or when myocardial washout is

Table 3 Tests for differences

in sensitivity and specificity

between WO INDx and WR for

WS2

WO INDx showed higher

sensitivity than WR and a

significant difference between 2

indices was found in sensitivity,

but not in specificity

Observer INDx WR Difference p value Confidence interval on difference

Lower

limit

Upper

limit

Sensitivity

1 0.893 0.536 0.357 0.024 0.051 0.663

2 0.889 0.528 0.361 0.024 0.052 0.67

3 0.963 0.519 0.444 0.031 0.082 0.807

Specificity

1 0.882 0.875 0.007 0.862 -0.073 0.088

2 0.898 0.794 0.104 0.062 -0.001 0.208

3 0.793 0.874 -0.081 0.097 -0.173 0.011

Fig. 1 Comparison of WO INDx and washout rate in a clinical case

Ann Nucl Med (2010) 24:713–719 717

123

slightly increased, it is also difficult to detect an abnormal

region from the whole myocardium using WR. In ischemic

heart disease, such as AMI and angina, stenosis in coronary

artery dominant region decreases the myocardial blood flow

to cause some abnormalities in cellular function. Especially

for MIBI, the washout of MIBI is enhanced at a high rate

when the mitochondrial function remains abnormal [21].

This enhanced washout has been evaluated using a differ-

ence of early image–delayed image based on the visual

score, but the evaluation using the visual score generally

varies among observers and is less objective. In this study, a

large difference in WR among patients is considered as a

factor causing low sensitivity in the evaluation with WR.

Thus, when WR is high in a normal region, it is impossible to

determine whether WR is normal or abnormal even in the

same patient. The analysis with WO INDx that we devel-

oped is characterized by the restandardization of %uptake

and can decrease the variation in WR among individuals.

In this examination, the SPECT image that was acquired

6 h after the tracer infusion was a delayed image [11]. It is

suggested that the image acquired after 6 h reflects an

abnormal area before the AMI reperfusion. The delayed

SPECT image 6 h later influences the image quality due to

the physical half-life of 99mTc. The delayed image of

normal persons was 113 counts on average on the anterior

planar image of the heart, and it was a minimum of 95

counts. There was no case including the clinical cases in

which the problem of image quality deterioration occurred.

In general, a region with %uptake of 60% or less is

generally regarded as an abnormal region and a region with

60% or higher is regarded as a normal region [22, 23].

However, %uptake is largely decreased even in a normal

region in some patients. We have experienced a case in

which no abnormal myocardial region was found although

there was a large difference in %uptake in the normal

region between early image and delayed image in the

control group. In this case, we need to pay attention to an

abnormal value of WO INDx even in a normal region and

should address this issue in the future.

In addition, it may be possible to evaluate mismatch

between myocardial perfusion and fatty acid metabolism or

between stress myocardial perfusion and myocardial per-

fusion at rest using the equation for WO INDx. The display

with %uptake can evaluate the difference between nor-

mal and abnormal regions objectively and quantitatively

regardless of nuclear species and could be used in various

clinical settings.

Conclusions

The results suggested that the diagnosis using a new index,

WO INDx, calculated from standardized percentage

uptakes is more useful than that using the washout rate

determined from the myocardial count in the MIBI wash-

out evaluation.

Acknowledgments We are grateful to three nuclear cardiology

specialists: Dr Futoshi Tadehara, Dr Tokuo Kasai and Dr Muneo

Ohba for their support with the visual evaluation of clinical cases. The

authors appreciate the technical assistance with the statistical analysis

and software development of Takehiro Ishikawa and Tetsuo Hosoya

of FUJIFILM RI Pharma Co., Ltd.

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