ISSN 0030- 6096

O S A K A
C I T Y

Vol.

68

No.2

M E D I C A L

2022

J O U R N A L

V o l . 6 8 ,N o . 22 0 2 2

PUBLISHED BYOSAKA CITY MEDICAL ASSOCIATIONOSAKA JAPANOsaka City Medical Journal
Vo l . 6 8 , N o . 2 ,December 2022

CONTENTS
Establishment of a Long-term Survival Model after Extracorporeal

page

Circulation in Rats
RYOJI SADA, YOSUKE TAKAHASHI, TOSHIHIKO SHIBATA,
TOMOHIRO NAKANO, and SYUJI INAMORI ･････････････････････････････････････････････････････････ 51
Correlation between Low Amount of Epicardial Adipose Tissue andthe Severity of Right Ventricular Dysfunction in Patients with
Nonischemic Heart Failure with Reduced Ejection Fraction
AKIKO TANIHATA, SHOICHI EHARA, RYOKO KITADA,
HIROTOSHI ISHIKAWA, TOSHITAKE YOSHIDA, HIROYA HAYASHI,YUMI YAMAGUCHI, ATSUSHI SHIBATA, YASUHIRO IZUMIYA,and DAIJU FUKUDA ･･････････････････････････････････････････････････････････････････････････････････････ 61
Association between Receiving Feedback on the Results ofan Automated Cognitive Function Test and Motivation for
Dementia-preventive Behavior
SATOSHI AKADA, KENTARO UCHIDA, JUMPEI MARUTA,
HIDEO KUROZUMI, SATOSHI NOGI, and KOKI INOUE ･･･････････････････････････････････････････ 73
A History of Obesity in Severe Anorexia Nervosa Predicts
Outpatient Treatment Dropout
MIHOKO HONDA, TOMOKO HARADA, TSUNEO YAMAUCHI,SAORI MIYAMOTO, TAKUMI MATSUZUKA, AKIHIRO MUI,NAOKI OHARA, and KOKI INOUE ･････････････････････････････････････････････････････････････････････ 81― Case Report ―Strangulated Small-bowel Obstruction due to Transmesosigmoid Hernia
Diagnosed with Multidetector Computed Tomography: A Case Report
TOHRU TAKESHITA, HISAKAZU MATSUSHIMA, KIMIMASA IKEDA,TOSHIKI NOMA, TAKUYA GOTO, and DAIJU UEDA ･･･････････････････････････････････････････････ 91

Osaka City Med. J. Vol. 68, 51-60, 2022

Establishment of a Long-term Survival Model
after Extracorporeal Circulation in Rats
RYOJI SADA1), YOSUKE TAKAHASHI1), TOSHIHIKO SHIBATA1), TOMOHIRO NAKANO2), and SYUJI INAMORI2)
Department of Cardiovascular Surgery1),
Osaka City University Graduate School of Medicine; andDepartment of Medical Engineering2), Junshin Gakuen University

Abstract
Background
The purpose of this study is to establish a long-term survival model in rats after extracorporeal
circulation.
Methods
SD rats (male, 400-600g) were used. To establish an extracorporeal circulation without
thoracotomy, an arterial cannula was inserted into the right common carotid artery with venous
drainage from the right internal jugular vein. The heart was then allowed to beat for 1 hour, followed
by forced ventilation during extracorporeal circulation. Hematocrit level was then examined between
the thoracotomy (n＝8) and non-thoracotomy groups (n＝8). To examine how tidal volume affects thesurvival period and organ damage, the non-thoracotomy group was divided into two groups based on
the tidal volume. The left ventricular diameter shortening rate was measured. After 30 days ofsurvival, rats were examined the pathophysiology of the left ventricle, lungs, and kidneys.
Results
In the non-thoracotomy group, the minimum hematocrit level was higher (30.8% vs 21.7%, p≦0.05)
compared to the thoracotomy group. Postoperative left ventricular diameter shortening rate wassignificantly different between the low and normal tidal volume groups (47.3% vs 36.1%, p≦0.05).
Pathological examination revealed bleeding due to congestion in the lungs of rats that survived 30
days after extracorporeal circulation. On the other hand, the kidneys and left ventricular collagenfiber density did not differ significantly.
Conclusions
A tidal volume might affect systolic left ventricular function during extracorporeal circulation.
Although pulmonary congestion was recognized on pathological findings, long-term survival was
successfully achieved using the non-thoracotomy model with a low tidal volume during extracorporeal
circulation.
Key Words: ‌Cardiopulmonary bypass; Chronic experiment model; Rat model
Received October 21, 2021; accepted April 12, 2022.
Correspondence to: Yosuke Takahashi, MD.
Department of Cardiovascular Surgery, Osaka Metropolitan University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3840; Fax: +81-6-6646-6057
E-mail: takahashi.yosuke@omu.ac.jp- 51 -

Sada et al

Introduction
Extracorporeal circulation (ECC) technology is essential for cardiovascular surgery and is now
used worldwide as an established procedure. These advancements resulted from various studies andimprovements by Dr. John Gibbon in 1953, who used the artificial heart-lung machine for
cardiovascular surgery1). Research on ECC technology has been conducted using large animals suchas goats and dogs because the devices used were so large that we could not perform this kind of study
on small animals2,3). In recent years, however, experiments using large animals have become difficult
to continue due to economic and ethical backgrounds. There is a growing need for experimental
systems using small animals such as mice and rats that can be supplied at low cost4,5).
Since 2005, we have been conducting experiments on rats using ECCs. In this experiment, ECC
was established by inserting an arterial cannula from the right common carotid artery and venous
cannula from the right atrium via median sternotomy. We found that pulsating perfusion for cerebral
microcirculation during ECC and suppression of neutrophil activity prevents lung damage after
ECC6-10). On the other hand, there was a problem of short survival in the rat ECC models. The reason
for this was related to the invasiveness of ECC establishment4,5). The invasion of open chest surgery
and artificial respiration may have caused heart failure and lung damage. We hypothesized that the
introduction of ECC in a non-open chest setting, as well as low tidal volume during ventilation, would
prolong survival in the rat model. The aim of this study was to create a long-term survival modelusing an ECC model with continuous cardiac contraction by making it less invasive. Furthermore,
we investigated whether tidal volume during ECC affects cardiac function and survival. Lastly,organ damage was examined pathologically in surviving samples.

Methods
In all experiments, we used SD male rats (10-13 weeks old, 400-600g, Japan SLC Co., Ltd., Tokyo).
Respiratory management was performed using a small animal ventilator (Respirator Model SN48D-7, Shinano Seisakusho Co., Ltd., Tokyo). The rat ECC system consisted of a closed circuit, heatexchanger, artificial lung (membrane area: 0.03 m2, filling volume: 2.0 mL manufactured by Senko
Medical Instrument mfg. Co., Ltd., Tokyo) (Fig. 1), and a roller pump (PERISTA Mini-Pump SJ-1211;
manufactured by ATTO Co., Ltd., Tokyo) (Fig. 1). The priming volume was summed up to 10 mL(Mannitol 2 mL, sodium bicarbonate 2 mL, and Ringerʼs solution 6 mL). The blood f low volume of the
ECC was 90 mL/kg/min, and the ratio of oxygen to carbon dioxide sent to the artificial lung was set to95: 5. Rectal temperature was controlled to be 37℃.
Experiment 1 (Establishment of non- thoracotomy rat model)
Anesthesia was induced by oxygen (1 L/min) and isof lurane (4.0%) using a dedicated box. A
14-gauge indwelling needle outer cylinder was inserted in the thoracotomy rat model (N＝8) from thetracheostomy. The non-thoracotomy rat model (N＝8) was subjected to endotracheal intubation using
a 14-gauge indwelling needle outer cylinder. Monitoring was done using electrocardiography, arterialpressure (canulation site of the common carotid artery), and rectal temperature. In the thoracotomy
rat model, the right common carotid artery was cut to insert the arterial cannula (outer diameter, 1.1
mm polyethylene tube). Systemic heparinization (1000 IU /kg) was performed from the arterial
cannula. Eighteen-gauge needle outer tube was inserted from the right atrium for drainage after amedian sternotomy. In the non-thoracotomy group, the venous cannula (18-gauge indwelling needle
outer cylinder) was placed in the right atrium using a guidewire from the right internal jugular vein.
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Long-term Survival Model in Rats

Figure 1. Layout of the experiment. After the right carotid artery and jugular vein were exposed, the arterial andvenous cannulas were inserted using the cut down method in the non-thoracotomy group. The tip of the venous
drainage tube was located in the right atrium. Venous drainage is sent to the artificial lung by a roller pump tooxygenize and subsequently sent to the right carotid artery.

Right common carotid artery was cut to insert the arterial cannula (outer diameter, 1.1 mm
polyethylene tube). Forced ventilation without spontaneous respiration was continued during partial
ECC in both groups. All data were measured just before cessation of ECC. The ventilator was set tohave an oxygen concentration of 100%, 2% isof lurane, 1:1 to I:E ratio, 90 beats per minute, and aventilation volume of 5 mL/kg to maintain arterial blood carbon dioxide pressure at approximately 40
mm Hg. To maintain acid-based equilibrium, sodium bicarbonate was administered as appropriate.
After continuing the ECC for one-hour, sufficient hemostasis was performed, and the arterial andvenous cannula were removed. The cervical incision was then ligated and closed. Isof luraneadministration was stopped, and sufficient spontaneous respiration was confirmed. Arterial blood gas
analysis, rectal temperature, operation time, intraoperative bleeding volume, and minimum
hematocrit level during ECC were compared between the two groups. The endotracheal tube was
extuvated and observed under room air to check the survival time in both groups. The survival rats
were euthanized 30 days after experiment.
Experiment 2
To study the effects of respiratory management during ECC on long-term survival, we performedExperiment 2. The protocols for anesthesia induction and ECC establishment were the same with
the non-thoracotomy group in experiment 1. After induction of anesthesia, the rats were placed in- 53 -

Sada et al

the lateral supine position. The diastolic left ventricle dimension and systolic left ventricle dimension
during spontaneous breathing were measured using an ultrasonographic apparatus (Nemio TMXG
SSA-580 A; Toshiba Medical Systems Co., Ltd., Tokyo). The fractional shortening rate (%FS) of theleft ventricle was also calculated (Fig. 2A).
The rat groups comprised of group A (n＝8; respiratory frequency, 90 bpm, single ventilation
volume: 5 mL/kg), which is a low tidal volume group and group B (n＝8; respiratory frequency,
60 bpm, single ventilation volume: 8 mL/kg), which is a normal range of tidal volume. The minuteventilation volumes of both groups were the same in both groups. After initiating ventilation, the%FS during positive pressure ventilation was measured. After weaning from ECC for one hour andextubating the endotracheal tube, %FS was measured again by echocardiography under spontaneous
respiration at rates of 70 bpm or more. After the operation, the survival time was measured using avideo camera under room air management in both groups. The rats were observed for 30 days, andexperiment 3 was performed on the surviving rats.
Experiment 3
Organ damage was examined in rats that survived for a long period of 30 days after Experiment 2.
We compared their rates with the control group. The rats in control group were also anesthetizedwith endotracheal intubation. We made cervical incision as the same manner as non-thoracotomy
group, and the incision was closed immediately without applying ECC. Rats were euthanized byinjecting an overdose of potassium. The heart, lungs, and kidneys were then removed to verify organ
damage by pathological diagnosis. After collecting the samples, the tissues from both groups were
fixed with 10% formalin, embedded in paraffin, and cut into 4 μm sections. After fixing the tissues,
the lungs and kidneys were stained with hematoxylin and eosin while the left ventricle was stainedwith Asan stain.
Animal preparation
In this study, breeding, handling, and experimental planning of laboratory animals were carriedout with the guidance and approval from Osaka City University Medical School Animal ExperimentCommittee based on animal experiment guidelines of Osaka City University (approval number
16016).
Statistical analysis
Data were expressed as median (25th-75th percentile). A Mann-Whitney U test was used forstatistical analysis to compare the groups using IBM SPSS Statistics (IBM Co., Ltd., Tokyo).
Statistical significance was set at p value ＜0.05.

Results
Experiment 1 (comparison between the thoracotomy group and the non-thoracotomy groupregarding peri-operative data) (Table 1)
The survival time was 720 (527-720) hours in non-thoracotomy group. There were no significant
differences in operating time, blood gas data just before end of the ECC, and central temperature
between the thoracotomy and non-thoracotomy groups. In the non-thoracotomy group, bleeding
quantity was lower [1.1 (0.9-1.4) mL) vs 5.9 (5.6-6.2) mL, p≦0.05)] while minimum hematocrit level
was higher [30.8 (28.9-32.2) % vs 21.7 (19.3-22.7) %, p≦0.05] compared to the thoracotomy group.
Experiment 2 (the %FS measurement between group A and B) (Fig. 2)
Group A had a preserved %FS and a significantly higher %FS than group B after weaning from- 54 -

Long-term Survival Model in Rats
Table 1. Data during experiment 1 between both groupsGroup
Operating time(min.)
PO2 (mmHg)

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8Median(25th-75th percentile)Thoracotomy

99

87

82

84

90

95

86

83

87 (84-89)

Non-thoracotomy

86

88

75

96

91

87

95

83

88 (85-93)

Thoracotomy

88

93

95

91

89

90

93

85

91 (89-93)

Non-thoracotomy

87

88

94

86

90

93

92

80

89 (87-93)

Thoracotomy

42

44

42

45

46

46

44

38

44 (42-46)

Non-thoracotomy

44

46

47

48

39

40

44

48

45 (43-48)

Thoracotomy
Rectumtemperature (℃) Non-thoracotomy

33.3

30.4

32.1

29.9

31.7

33

32.5

31.8

32.0 (31.4-32.3)

33.6

30.6

32.4

31.5

32.8

33

30.4

29.9

32.0 (30.6-32.6)

Bleeding volume Thoracotomy(mL)
Non-thoracotomy

5.2

5.4

5.7

5.8

5.9

6

6.4

6.6

5.9 (5.6-6.2)

0.8

0.8

0.9

1

1.2

1.3

1.4

1.4

1.1 (0.9-1.4)＊

PCO2 (mmHg)

Thoracotomy

4

7

11

8

6

5

5

7

7 (5-8)

576

720

720

384

720

720

240

720

720 (527-720)

23.1

22.2

24.1

21.7 (19.3-22.7)

30.2

28.7

29

30.8 (28.9-32.2)＊

Survival time(hours)

Non-thoracotomy

Minimum Hctlevel (%)

Thoracotomy

18.5

22

21.4

17.6

19.5

Non-thoracotomy

31.6

33

28.6

31.4

34.3

＊

p≦0.05. Hct, hematocrit.

Table 2. Data during experiment 2 between both groups
Group Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8
Operating time(min.)
PO2 (mmHg)

PCO2 (mmHg)

Median(25th-75th percentile)

A

85

78

80

86

95

84

77

75

82 (78-85)

B

83

88

86

75

74

86

82

82

83 (80-86)

A

111

104

92

88

117

99

91

110

102 (92-107)

B

108

115

110

118

99

106

112

111

111 (108-114)

A

46

41

39

38

40

42

45

42

42 (40-42)

B

38

38

40

42

36

35

36

39

38 (36-40)

Rectum temperature
(℃)

A

32.1

30.8

30.5

32.2

31.6

32.8

33

31.8

32.0 (31.4-32.5)

B

32.4

33.1

31.5

32.8

31

30.8

31.5

30.4

31.5 (31.0-32.2)

Airway pressure(cmH2O)

A

13

14

12

14

15

12

12

13

13 (12-14)

B

15

17

13

14

15

15

16

14

15 (14-16)

Bleeding volume
(mL)

A

1

1.4

0.8

1.1

1.5

1

0.8

1.3

1.1 (1.0-1.4)

B

0.9

0.8

1.2

1.1

1.8

1.6

0.9

1.1

1.1 (0.9-1.4)

Survival time(hours)

A

720

720

528

720

439

720

720

720

720 (672-720)

B

8

12

24

17

30

8

42

22

20 (11-27)＊＊p≦0.05.

ECC. The %FS under spontaneous respiration before ECC was 51.1 (49.4-51.9) % in group A and 50.1
(48.7-51.8) % in group B, showing no significant difference between groups. On the other hand, %FS
was 47.3 (45.1-48.5) % in group A and 36.1 (35.1-36.3) in group B after ECC, which showedsignificantly lower %FS values in group B (p≦0.05) (Fig. 2B). The survival time in group A was better
than that in group B (720 (672-720) hours vs 20 (11-27) hours, p≦0.05). In group A, six out of eightrats achieved 30-day survival after weaning from ECC (Table 2).
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Sada et al

Figure 2. (A) M-mode imaging of echocardiogram. The image on the left is group A and the right is group B. diastolicdimension (a) and systolic dimension (b).
(B) Box plots showing %FS in both groups before ECC and just after ECC. Black box indicates the %FS in group A
and grey box indicates the %FS in group B. The %FS just after surgery was worse than that before ECC in group B (p＜0.05). %FS is calculated by (LVDd-LVDs) / LVDd×100. FS, fractional shortening; and ECC, extracorporeal circulation.

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Long-term Survival Model in Rats

Figure 3. Photomicrophotograph of the left lung (A), left kidney (B) and left ventricle (C). The control group is
depicted on the left and the group with 30 days survival on the right. The left lung and left kidney were stained byhematoxylin and eosin with original magnification×20. The heart section was stained by Asan stain with original
magnification×40. Increased density of alveolar epithelium and multinucleated giant cell in the lung are shown in thegroup with 30 days survival. There is no pathologically difference in kidney between groups. There is no difference
regarding collagen fiber in the left ventricle between groups. Black arrow shows plasma components lightly stainedwith eosin in the alveoli. Red arrow shows red blood cells in the alveoli, indicating bleeding.

- 57 -

Sada et al

Experiment 3 (pathological examination of rat organs) (Fig. 3)
Figure 3 compares the pathological images of the survival cases and the control group. In thesurvival cases, local emphysema, red blood cell infiltration, swelling of the pulmonary capillaries, andtransudate bleeding in the alveoli were observed; these findings were not observed in the control
group. Macrographic findings showed that dilatation of the left ventricular cavities and thinning of
the left ventricular wall were observed in survival cases. On the other hand, there was no differencein the left ventricular wallʼs collagen fiber density between survival cases and the control group.
There were also no significant differences in the kidneys of the two groups.

Discussion
In this experiment, 1) we established a rat model of long-term survival after weaning from ECC. 2)
The %FS was maintained within the normal range in rats with reduced tidal volume during ECC. 3)
Pathological findings showed pulmonary congestion and cardiac enlargement in a rat model of longterm survival.
We have been conducting experiments on ECC using rats since 2011, which is an acute
experimental model11-13). Bleeding quantity in the non-thoracotomy model that did not require bothtracheostomy and median sternotomy was significantly lower compared to the thoracotomy model.
The cause of anemia in the thoracotomy model is bleeding from the sternum due to systemic
heparinization. To establish a chronic model, it is necessary to maintain stable hemodynamics during
and after ECC. Therefore, it is mandatory to establish an experimental model with less bleeding. By
devising the cannulation method without thoracotomy, we were able to establish a less invasivechronic rat model.
Differences in respiratory management during ECC significantly affected postprocedural cardiac
function. Our experiment involved ECC with assisted beating heart circulation under forced
ventilation. After ECC, the %FS in group B, which had a higher tidal volume, was 36.1 (35.1-36.3) %.
From this result, we considered that it is better to use a low tidal volume with increased respiratory
rate while maintaining the minute volume, to prevent postoperative cardiac suppression.
Conventionally, the effect of positive pressure ventilation in humans differs greatly between the rightand left ventricles. Since increased intrathoracic pressure compresses the right ventricle, venous
perfusion was suppressed, and the preload of the left ventricle decreased. The decrease of the preloadof the left ventricle has little effect on left ventricular tension and afterload14,15). However, when ahigh intrathoracic pressure is continuously exposed to inappropriate respirator settings, there will be
an increase in afterload of the left ventricle and a decrease in cardiac function16). In fact, even inhumans, cardiac suppression is reported to range from 14.5% to 16.5% due to positive pressure
ventilation using a respirator17). Based on these, it is necessary to consider appropriate tidal volume
settings.
Injuries to vital organs caused by ECC and ventilator itself have been reported, including elevatedlevels of inf lammatory cytokines and damage caused by reactive oxygen species18-20). Lung injury
caused by ventilator is also considered to one of the reasons that affected survival21,22). We consider
that lung injury via barotrauma, volutrauma and biotrauma due to positive pressure ventilation
might affect the survival of the rat.
In this study, pathological findings showed no ischemic findings in the kidneys due to ECC.
However, mild pulmonary congestion and left ventricular dilatation in long-term survival cases- 58 -

Long-term Survival Model in Rats

showed that elevated afterload caused by ECC might affect the lungs and left ventricle. Persistently
high intrathoracic pressure reduces venous return in the right heart system but increases pulmonary
vascular resistance, which ultimately surpasses left atrial pressure16). As a result, venous return andcardiac output from the left ventricle is expected to increase. However, deformity of theinterventricular septum due to increased right ventricular pressure and elevated afterload mightworsen %FS, pulmonary congestion, and left ventricular function. This may be one of the reasons
why long-term survival could not be obtained in the group where the tidal volume was larger. It wasalso suggested that the possible cause of pulmonary congestion and cardiac dilatation may include
ECC invasion, ventilator-induced lung injury, and associated reactive oxygen species and inf lammatory
cytokines. A more stable rat model of long-term survival may be constructed by adjusting to theappropriate tidal volume or creating a less invasive ECC model that maintains spontaneous
respiration regardless of the presence of a respirator synchronized with spontaneous respiration.
ECC applied to humans can now be performed safely. However, cerebral complications and organ
damage, including the lung and heart associated with ECC, will likely develop. It is necessary to
conduct further studies regarding the detailed pathophysiological organ damage caused by ECC.
Establishing a long-term survival model of ECC by our research might be useful for a wide range ofstudies because various non-physiological conditions can be added during ECC in small animals thatare inexpensive and easy to handle. In addition, circulatory dynamics management can be performed
safely by considering the appropriate tidal volume setting on the respirator in clinical settingsrequiring percutaneous cardiopulmonary support.

Limitations
Since the number of cases is small, it is necessary to conduct further experiments in the future.
Second, cardiac function was evaluated at two points only: before ECC and immediately after the endof ECC. Therefore, it is necessary to evaluate whether the decreased cardiac function is temporary orsustained by measuring several points after ECC. Thirdly, it would be very useful to quantify thetissue evaluation of the lungs and heart as an objective indicator. It would be easier to understandthe results if we could quantify them, but we have not been able to do so in this experiment. We areplanning to quantify the tissue evaluation in the next research. Lastly, although a successful longterm survival model after ECC was established, pathological myocardial and pulmonary damage
occurred. We consider that there is room for further improvement, such as setting tidal volume and
ECC management regarding volume support and blood pressure control.
Acknowledgement
All authors have no COI to declare regarding the present study. This work was supported by
JSPS KAKENHI (Grant Number 17K11601).
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12. Fujii Y, Shirai M, Inamori S, et al. A novel small animal extracorporeal circulation model for studying
pathophysiology of cardiopulmonary bypass. J Artif Organs 2015;18:35-39.
13. Fujii Y, Tanabe T, Yamashiro T, et al. Effect of hydroxyethyl starch priming on the systemic inf lammatory
response and lung edema after cardiopulmonary bypass in a rat model. ASAIO J 2017;63:618-623.
14. Pinsky MR, Summer WR. Cardiac augmentation by phasic high intrathoracic pressure support in man. Chest
1983;84:370-375.
15. Pinsky MR, Summer WR, Wise RA, et al. Augmentation of cardiac function by elevation of intrathoracic
pressure. J Appl Physiol Respir Environ Exerc Physiol 1983;54:950-955.
16. Cheifetz IM. Cardiorespiratory interactions: the relationship between mechanical ventilation andhemodynamics. Respir Care 2014;59:1937-1945.
17. Cournand A, Motley HL. Physiological studies of the effects of intermittent positive pressure breathing on
cardiac output in man. Am J Physiol 1948;152:162-174.
18. Orhan G, Yapici N, Yuksel M, et al. Effects of N-acetylcysteine on myocardial ischemia-reperfusion injury in
bypass surgery. Heart Vessels 2006;21:42-47.
19. Fujii Y, Shirai M, Tsuchimochi H, et al. Hyperoxic condition promotes an inf lammatory response during
cardiopulmonary bypass in a rat model. Artif Organs 2013;37:1034-1040.
20. Zakkar M, Guida G, Suleiman M-S, et al. Cardiopulmonary bypass and oxidative stress. Oxid Med Cell Longev
2015;2015:189863.
21. Lentsch AB, Czermak BJ, Bless NM, et al. Essential role of alveolar macrophages in intrapulmonary activationof NF-kappaB. Am J Respir Cell Mol Biol 1999;20:692-698.
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Osaka City Med. J. Vol. 68, 61-72, 2022

Correlation between Low Amount of Epicardial Adipose Tissue andthe Severity of Right Ventricular Dysfunction in Patients with
Nonischemic Heart Failure with Reduced Ejection Fraction
AKIKO TANIHATA1), SHOICHI EHARA2), RYOKO KITADA2), HIROTOSHI ISHIKAWA2), TOSHITAKE YOSHIDA1),
HIROYA HAYASHI1), YUMI YAMAGUCHI2), ATSUSHI SHIBATA2), YASUHIRO IZUMIYA2), and DAIJU FUKUDA2)
Department of Cardiovascular Medicine1),
Osaka City University Graduate School of Medicine; andDepartment of Cardiovascular Medicine2),
Osaka Metropolitan University Graduate School of Medicine

Abstract
Background
Although epicardial adipose tissue (EAT) volume is associated with coronary artery disease andatrial fibrillation, the clinical role of EAT in heart failure (HF) remains controversial. In patientswith HF with reduced ejection fraction (HFrEF), right ventricular (RV) dysfunction is associated with
impaired functional capacity. This study aimed to investigate the relationship between the EAT
volume and RV systolic function in patients with HFrEF.
Methods and Results
A total of 100 consecutive patients with nonischemic HF who had undergone cardiac magnetic
resonance imaging and computed tomography were enrolled. First, patients were categorized basedon the left ventricular (LV) EF; patients with LVEF ≧50% and LVEF ＜50% were classified into the
HF with preserved EF (HFpEF) (n＝14) and HFrEF (n＝86) groups, respectively. Then, the HFrEF
group was further divided into the HFrEF with RV dysfunction (RVEF ＜45%, n＝54) and HFrEF
without RV dysfunction (RVEF ≧45%; n＝32) groups. The EAT volume indexed to body surface area
(BSA) in the HFrEF with RV dysfunction group was significantly lower than that in the other groups.
In the HFrEF group, EAT volume indexed to BSA was positively correlated with RVEF (r＝0.28, p＜0.01) but not with LVEF. Multivariate analysis revealed that LVEF and EAT volume indexed to BSA
were independent factors associated with HFrEF with RV dysfunction.
Conclusions
This study demonstrated that HFrEF patients with RV dysfunction had less EAT compared to
HFpEF patients, and less amount of EAT was related to the severity of RV dysfunction in HFrEF.
Key Words: ‌Epicardial adipose tissue, Heart failure, Right ventricular failure,
Magnetic resonance imaging
Received February 21, 2022; accepted June 14, 2022.
Correspondence to: Shoichi Ehara, MD.
Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3801; Fax: +81-6-6646-6808
E-mail: ehara@omu.ac.jp- 61 -

Tanihata et al

Introduction
The concept of cardiac adiposity as a novel cardiovascular risk factor has recently received
increasing attention. Epicardial adipose tissue (EAT) is a unique and multifaceted visceral fat depot
and has anatomic and biomolecular relationship with the heart. The functional and anatomic
proximity of EAT to the coronary artery and myocardium enables endocrine, paracrine, and vasocrine
effects on the heart. Previous studies have shown that EAT volume is associated with obesity1),
metabolic syndrome 2,3), insulin resistance 4), atrial fibrillation 5,6), and coronary artery disease7,8).
However, the clinical role of EAT in heart failure (HF) remains controversial9). This confusion may be
attributed to the heterogeneity of HF in terms of classification, stage, and severity.
It has been proposed that left ventricular (LV) remodeling in HF with reduced ejection fraction(HFrEF) is driven by the progressive loss of cardiomyocytes, which results from ischemia, infection, or
toxicity10). Although nonischemic HFrEF, especially dilated cardiomyopathy, is a primary heart
muscle disease characterized by LV cavity enlargement and impaired contractility, right ventricular(RV) systolic dysfunction is frequently observed during the initial evaluation. In patients with
HFrEF, RV systolic dysfunction is associated with impaired functional capacity and is a key factor in
determining prognosis11). However, most EAT-related studies have analyzed only LV function andpaid less attention to RV function12-14). One of the reasons is that the RV has a complex shape, and it
is difficult to estimate RV volume and function.
Cardiac magnetic resonance (CMR) imaging is the most accurate method for evaluating RVvolume and function15). Furthermore, multidetector computed tomography (MDCT) can provide amore accurate and volumetric measurement of EAT compared with echocardiography. This study
aimed to compare the EAT volume among patients with nonischemic HFrEF, patients with preserved
ejection fraction (HFpEF), and control subjects, and to investigate the relationship between the EAT
volume and RV systolic function in patients with nonischemic HFrEF.

Methods
The study was approved by the hospital ethics committee, and informed consent of patients was
obtained according to the institutional review board policies regarding hospital administration(approval no.3785).
Study population
This single-center retrospective observational study enrolled 100 consecutive patients with newly
diagnosed nonischemic HF who visited our institution for the evaluation of cardiac dysfunction or
management of HF and underwent CMR imaging and MDCT between September 2017 and April
2021. To be diagnosed with HF, all patients had to satisfy two major or one major and two minor
Framingham criteria16). The exclusion criteria were as follows: i) significant coronary artery disease(defined as the presence of ≧70% luminal stenosis in an epicardial coronary artery or any history of
myocardial infarction or coronary revascularization), ii) severe valvular heart disease, iii) infiltrative
cardiomyopathy, iv) sarcoidosis, v) amyloidosis, vi) hypertrophic cardiomyopathy, vii) myocarditis,viii) permanent pacemaker, implantable cardiac defibrillator, or cardiac resynchronization therapy,ix) uncontrolled insulin dependent diabetes mellitus, x) severe renal dysfunction with estimatedglomerular filtration rate ＜30 mL/min/1.73m2. First, patients were categorized based on the LV
ejection fraction (LVEF) measured by CMR; patients with LVEF ≧50% and LVEF ＜50% wereclassified into the HFpEF and HFrEF groups, respectively. The HFrEF group was then further- 62 -

Correlation between EAT and RV Dysfunction in HFrEF

divided into the HFrEF with RV dysfunction (RVEF ＜45%) and HFrEF without RV dysfunction(RVEF ≧45%) groups17). The HFrEF group was treated with beta-blockers, angiotensin-converting
enzyme inhibitors, or angiotensin Ⅱ receptor blockers unless contraindicated. Furthermore, we
included 50 individuals matched for age, sex, and body mass index (BMI), including 35 men and 15
women with a mean age of 57±12 years and BMI of 23.3±4.0, as controls to evaluate EAT volume.
The control group satisfied the following criteria: normal physical examination; normal
electrocardiographic findings; no significant coronary stenosis on MDCT; no history of HF, myocardial
infarction, or coronary revascularization; and normal 2D echocardiographic and Doppler examination
results.
Data on age, sex, and the presence of risk factors (such as smoking and hypertension, as definedby the Joint National Committee Ⅶ; diabetes mellitus, as defined by the World Health Organization
study group; or dyslipidemia, as defined by the Japan Atherosclerosis Society guidelines) were alsocollected.
CMR image acquisition and analysis
CMR images were acquired using a 1.5-T MR imager (Achieva, Philips Medical Systems, Best, theNetherlands) with a 32-element cardiac coil. Cine MR studies were conducted using steady-state
free-precession sequence at the shortest possible repetition/echo time and at a f lip angle of 55°or 60°
along the LV vertical long-axis. By presenting a 4-chamber view and a sequential 10-mm short-axis(no gap) from the aortic valve ring to the apex, these studies allowed for the evaluation of structuraland functional assessment.
LVEF and RVEF were calculated by short-axis cine MR imaging, performed under clinically stableconditions, using Simpsonʼs method15). LV and RV volumes were quantified by planimetry of the enddiastolic and -systolic endocardial borders on short-axis cine CMR images acquired from base to apex,
and were indexed to body surface area (BSA). EF was calculated as the difference between endsystolic volume and end-diastolic volume divided by end-diastolic volume. CMR analyses were
performed by an experienced physician (R.K) who was blinded to the clinical information using an
off line workstation (View Forum, Philips Medical Systems).
Acquisition of CT data for the assessment of EAT
All MDCT scans were performed using a 64-slice CT scanner (LightSpeed VCT VISION, GE
Healthcare Japan Co, Tokyo, Japan). Images were acquired during a single breath hold using
prospective ECG gating with imaging triggered at 75% of the R-R interval (collimation, 64×0.625
mm; tube voltage, 120 kV; gantry rotation time, 350 ms; tube current, 200 mA). Reconstructed axial
images of 2.5-mm thickness were transferred to an off line workstation (Synapse Vincent, Fujifilm
Medical Co, Tokyo, Japan) for image post-processing and analysis. The pericardium counter was
manually traced on each transaxial CT slice, followed by automated processing of all continuous
voxels with a density range of −200 to −30 Hounsfield units (HU) within the pericardial sac. The
upper border and lower border of EAT were considered at the bifurcation of the pulmonary trunk andat the LV apex, respectively. A region of interest was placed within the visceral epicardium todetermine EAT area, and the total EAT volume was calculated as the sum of the EAT area on eachslice multiplied by the thickness and number of slices5). EAT volumes were indexed to BSA or BMI.
EAT volumes were analyzed by an experienced physician blinded to other information (T.Y).
Clinical measurements
In patients with HF, baseline clinical parameters were obtained from hospital records, including- 63 -

Tanihata et al

laboratory analyses [serum brain natriuretic peptide (BNP) and high sensitivity C-reactive protein
levels] at hospital discharge. The LV diastolic function (mitral peak E and A velocities, E/A ratio, eʼ,and E/eʼ ratio, and deceleration time) and left atrial volume were assessed by echocardiography
performed under clinically stable conditions.
Statistical analyses
Continuous variables are presented as mean±standard deviation for normally distributed data
and as median and interquartile range for non-normally distributed data. BNP level data were notnormally distributed; therefore, log-transformed values of BNP level were used for all analyses.
Continuous variables were compared among the three groups using one-way analysis of variance(ANOVA), followed by a multiple comparison using post-hoc Tukey test. Categorical variables werecompared using Pearsonʼs χ2 test. Correlations among continuous variables were assessed using theSpearman rank-correlation coefficient. Multivariate logistic regression analyses were performed to
identify independent factors associated with HFrEF with RV dysfunction. Univariate predictors witha p value ＜0.10 were included in the multivariate model. A two-tailed p value ＜0.05 was considered
statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center,
Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (the R Foundationfor Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R designed to
add statistical functions frequently used in biostatics.

Results
A total of 100 patients were classified into the HFpEF (n＝14, 14%) and HFrEF (n＝86, 86%)
groups. In the HFrEF group, there were 54 patients (63%) with RV dysfunction (RVEF ＜45%,
HFrEF with RV dysfunction group) and 32 patients (37%) without RV dysfunction (RVEF ≧45%,
HFrEF without RV dysfunction group). The interobserver variabilities for LVEF and RVEF
measurements performed in a random sample of patients were 4.5±1.6% (r2＝0.995, p＜0.0001) and6.2±4.9% (r2＝0.995, p＜0.001), respectively. The intraobserver variabilities were 2.8±2.2% (r2＝1, p＜
0.0001) and 2.8 ±1.9% (r 2＝0.997, p ＜0.0001), respectively. Table 1 shows the baseline clinicalcharacteristics, echocardiographic data, and CMR data in the HFpEF, HFrEF with RV dysfunction,and HFrEF without RV dysfunction groups. There were no significant differences among the threegroups regarding age, gender, BMI, and coronary risk factors except diabetes mellitus. The HFrEF
with RV dysfunction group had significantly lower systolic blood pressure and higher heart rates
than the HFrEF without RV dysfunction or the HFpEF group. Regarding echocardiographic
parameters of LV diastolic function, the HFrEF with RV dysfunction group had significantly higher
E/A ratio and lower peak A velocity and deceleration time than the HFrEF without RV dysfunctiongroup. The HFrEF group showed significantly higher LV end-diastolic and LV end-systolic volume
index and lower LVEF than the HFpEF group. The HFrEF with RV dysfunction group had
significantly higher RV end-diastolic and RV end-systolic volume index and lower RVEF than the
HFrEF without RV dysfunction group. Medications at discharge were significantly different among
the three groups.
Figure 1 compares EAT volume and EAT volume indexed to BSA or BMI among the HFpEF,
HFrEF, and control groups. The EAT volume in the HFrEF group was significantly lower than thatin the HFpEF group (ANOVA: p＜0.05; Fig 1A). The EAT volume indexed to BSA or BMI in the
HFrEF group was also significantly lower than that in the HFpEF group (indexed to BSA, ANOVA: p- 64 -

Correlation between EAT and RV Dysfunction in HFrEF
Table 1. Baseline characteristics
HFpEF(n＝14)

HFrEF without
RV dysfunction(n＝32)

HFrEF with
RV dysfunction(n＝54)p

63±18
9 (64%)

60±16
19 (59%)57±1435 (65%)0.37
0.8

Hypertension, n (%)
Dyslipidemia, n (%)
Diabetic mellitus, n (%)

24.6±3.5
7 (50%)
5 (36%)
0 (0%)

23.2±4.1
15 (47%)
12 (38%)11 (34%)22.2±4.3
21 (39%)11 (20%)10 (19%)

0.25
0.66
0.2

Current Smoking, n (%)
Systolic blood pressure, mm Hg

6 (43%)
113.3±14.4

5 (16%)

14 (26%)0.13

120.2±18.9108.5±17.7＜0.05

Diastolic blood pressure, mm Hg

78.8±18.0

83.4±17.978.2±16.8

0.38Heart rate, bpm

63.5±11.6

70.6±14.375.3±16.5＜0.05

Atrial fibrillation, n (%)
Laboratory data
Hemoglobin, g/dL

4 (29%)

3 (9%)

8 (15%)

0.28
0.32

Age, years
Men, n (%)
Body mass index, kg/m2＜0.05

13.4±1.713.3±3.1

14.1±2.2

Hemoglobin A1c, mg/dL

5.7±0.4

6.0±0.6

6.2±1.6

0.4

BNP, pg/mL

180±211Log BNPC-reactive protein, mg/dL

1.93±0.60
0.16±0.18160±1841.96±0.49249±2352.18±0.47

0.16
0.07

0.17±0.30

0.13±0.17

0.75

Echocardiographic parameters
Left atrial volume, mL

0.46

66.1±23.9

59.6±22.6

65.7±23.4

Peak E velocity, cm/s

74.6±20.1

63.1±23.4

75.5±24.6

0.06

Peak A velocity, cm/s

86.3±28.63

70.0±21.6

58.5±19.6＜0.001＜0.05

E/A ratio

0.92±0.48

0.95±0.47

1.39±0.75

è, cm/s

4.8±2.2

4.6±1.94.8±2.0

0.9

E/è ratio19.1±12.9

14.8±4.818.1±9.7

0.19

Deceleration time, msec

245±98197±76160±60＜0.0012 (14%)
0 (0%)
1 (7%)

6 (19%)
1 (3%)
0 (0%)

12 (22%)0 (0%)
2 (4%)

0.83-

Moderate
Mitral valve regurgitation
Aortic valve regurgitation
Tricuspid valve regurgitation
CMR parameters
LV ejection fraction, %59.6±7.831.1±7.824.4±9.0＜0.001

2

LV EDVI, mL/m

78.7±20.1

124.9±32.9

135.9±45.4＜0.001

LV ESVI, mL/m2

88.0±30.3

104.9±42.2＜0.001

RV ejection fraction, %32.7±12.452.8±13.5

53.0±5.931.7±8.7＜0.001RV EDVI, mL/m2

89.6±35.7

68.7±14.3

101.7±38.3＜0.001RV ESVI, mL/m2

45.6±29.5

37.1±29.0

71.1±34.4＜0.001

Medication at discharge
β blocker, n (%)

9 (64%)

28 (88%)50 (93%)＜0.05

ACE inhibitors/ARB, n (%)
MRB, n (%)

10 (71%)
4 (29%)

25 (78%)18 (56%)43 (80%)38 (70%)＜0.05

Tolvaptan, n (%)
Loop diuretics, n (%)

2 (14%)
8 (57%)

1 (3%)
15 (47%)4 (7%)
38 (70%)

0.40
0.09

0.75

Values are mean±SD, n (%), or median (interquartile range). HFpEF indicates heart failure with preserved ejection
fraction; HFrEF, heart failure with reduced ejection fraction; RV, right ventricular; BNP, brain natriuretic peptide;
CMR, cardiac magnetic resonance; LV, left ventricular; EDVI, end-diastolic volume index; ESVI, end-systolic volume
index; ACE, angiotensin converting enzyme; ARB, angiotensin Ⅱ type 1 receptor blockers; and MRB, mineralocorticoid
receptor blocker.

- 65 -

Tanihata et al

Figure 1. (A) EAT volume, (B) EAT volume indexed to BSA, and (C) EAT volume indexed to BMI in the HFpEF,
HFrEF, and control groups. (D) EAT volume, (E) EAT volume indexed to BSA, and (F) EAT volume indexed to BMI in
the HFpEF, HFrEF without RV dysfunction, HFrEF with RV dysfunction, and control groups. EAT, epicardial adipose
tissue; BSA, body surface area; BMI, body mass index; HFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction; and RVD, right ventricular dysfunction.

- 66 -

Correlation between EAT and RV Dysfunction in HFrEF

Figure 2. In the HFrEF group, the correlation of EAT volume indexed to BSA or BMI with LVEF or RVEF. (A) EAT
volume indexed to BSA vs LVEF, (B) EAT volume indexed to BSA vs RVEF. (C) EAT volume indexed to BMI vs LVEF,(B) EAT volume indexed to BMI vs RVEF. HFrEF, heart failure with reduced ejection fraction; EAT, epicardial adipose
tissue; BSA, body surface area; BMI, body mass index; LVEF, left ventricular ejection fraction; and RVEF, rightventricular ejection fraction.

Table 2. ‌Univariate and multivariate analyses for association with HFrEF with RV dysfunction inpatients with HF
Univariate analysis

Multivariate analysis

Factors

OR

95% CI

p-value

Systolic blood pressure
Log BNP

0.97
2.62

0.95-0.99
1.13-6.1

＜0.05

OR

95% CI

p-value＜0.05

Deceleration time

0.99

0.98-1.00＜0.005

LV ejection fraction

0.90

0.86-0.94＜0.0010.90

0.84-0.95＜0.001

EAT volume
indexed to BSA

0.97

0.96-0.99＜0.001

0.97

0.95-0.99＜0.01

HFrEF indicates heart failure with reduced ejection fraction; RV, right ventricular; HF, heart failure; BNP, brain
natriuretic peptide; LV, left ventricular; EAT, epicardial adipose tissue; BSA, body surface area; OR, odds ratio; and CI,
confidence interval.

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Tanihata et al

Figure 3. CT showing EAT in representative cases of HFpEF, HFrEF without RV dysfunction, and HFrEF with RVD.
(A) CT showing abundant EAT surrounding the heart in a patient with HFpEF. (B) CT showing intermediate amountof EAT surrounding the heart in a patient with HFrEF without RVD. (C) CT showing very little EAT surrounding theheart in a patient with HFrEF with RVD. CT, computed tomography; EAT, epicardial adipose tissue; HFpEF, heart
failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and RVD, rightventricular dysfunction.

＜0.005; indexed to BMI, ANOVA: p＜0.05, Fig 1B and C). Moreover, the EAT volume in the HFrEF

with RV dysfunction group was significantly lower than in the HFpEF group (HFrEF with RV
dysfunction, 75.57±35.7 mL; HFrEF without RV dysfunction, 104.1±66.1 mL, HFpEF, 126.0±61.4
mL; and controls, 99.0±47.2 mL; ANOVA: p＜0.005; HFrEF with RV dysfunction vs HFpEF, p＜0.01;
Fig. 1D). The EAT volume indexed to BSA in the HFrEF with RV dysfunction group was significantly
lower than that in the other groups (HFrEF with RV dysfunction, 44.70±19.2 mL/m2; HFrEF without
RV dysfunction, 62.0 ±35.2 mL/m 2, HFpEF, 77.9 ±38.0 mL/m 2; and controls, 58.6 ±25.0 mL/m 2;
ANOVA: p＜0.001; HFrEF with RV dysfunction vs HFrEF without RV dysfunction, p＜0.05; andHFrEF with RV dysfunction vs HFpEF, p＜0.001; Fig 1E). There was no significant difference in EAT
volume and index between the HFpEF and control groups. As shown in Figure 2, the EAT volume
indexed to BSA or BMI in the HFrEF group was positively correlated with RVEF (indexed to BSA, r＝- 68 -

Correlation between EAT and RV Dysfunction in HFrEF

0.28, p＜0.01; indexed to BMI, r＝0.26, p＜0.05; Fig 2B and D), but not with LVEF (indexed to BSA, r＝0.068, p＝0.54; indexed to BMI, r＝0.08, p＝0.46; Fig 2A and C). In contrast, the EAT volume indexedto BSA or BMI in the HFpEF group was not significantly correlated with LVEF or RVEF. In patientswith HF, univariable and multivariable analyses were performed to identify the independent factors
associated with HFrEF with RV dysfunction (Table 2). Multivariable analysis revealed that LVEF
and EAT volume indexed to BSA were independent factors associated with HFrEF with RV
dysfunction. Figure 3 shows representative CT images assessing EAT in the HFpEF, HFrEF without
RV dysfunction, and HFrEF with RV dysfunction groups. Figure 3-A shows abundant EAT
surrounding the heart in a patient with HFpEF. In contrast, Figure 3-C and Figure 3-B show very
little EAT in an HFrEF patient with RV dysfunction and intermediate amount of EAT in an HFrEF
patient without RV dysfunction, respectively.

Discussion
To the best of our knowledge, this is the first study to investigate the correlation between theamount of EAT and RV function in patients with HFrEF. The major finding of this study was that
HFrEF patients, especially those with RV dysfunction, had less EAT volume index compared to
HFpEF patients or control patients despite similar BMI. Furthermore, the EAT volume index in the
HFrEF group was positively correlated with RVEF but not LVEF. Multivariable analysis revealed
that EAT volume index was an independent factor associated with HFrEF with RV dysfunction.
Some studies have shown that EAT is significantly reduced in patients with HFrEF compared tothat in the healthy controls12-14). Our data support those findings. The association between EAT andmechanisms responsible for the progression of HFrEF remains unclear. González et al proposed thatmyocardial dysfunction and remodeling in patients with HFrEF were driven by the progressive lossof cardiomyocytes22). This loss of cardiomyocytes results from various modes of cell death, such as
exaggerated autophagy, apoptosis, or necrosis, all of which are triggered by oxidative stress present
within the cardiomyocytes because of ischemia, infection, or toxic agents. As the myocardium
becomes more dysfunctional and develops abnormal metabolic needs, EAT satisfies its energy
requirements. EAT exhibits a high lipolytic activity and might serve as a ready source of free fatty
acids, leading to a decrease in EAT23). However, data regarding the correlation between LVEF and theamount of EAT are complicated and controversial. Some studies have reported the EAT volume
measured by CT or echocardiography to be positively correlated with LVEF12,13). On the contrary,
Doesch et al demonstrated a negative correlation between LVEF and EAT volume index, measured
using CMR imaging14). This disagreement may ref lect a difference in study population and theseverity of HFrEF. In patients with HFrEF, RV systolic dysfunction is associated with impaired
functional capacity and represents a more advanced stage11). However, RV function was not taken
into account in previous EAT-related studies. Therefore, the current study considered RV function
and observed that EAT volume index was positively correlated with RVEF (i.e., the worse the RV
function was, the lower the EAT volumes were). A postmortem study by Schejbal showed thatpersistent RV failure was associated with thinning of the surrounding fatty layer24). At an early stageof HFrEF, preserved vascular distensibility maintains pulmonary vascular resistance within thenormal ranges. However, as disease progresses, long-standing left atrial hypertension results in an
increase in RV afterload, which intern leads to RV dysfunction25). Therefore, at a more advanced stageof HFrEF, the lipolytic activity of EAT increases with a diminished responsiveness to adjust to the- 69 -

Tanihata et al

special energy demands of the heart, which may decrease EAT volumes.
On the contrary, several lines of evidence have suggested that an increase in EAT is significantly
related to a proportional increase in LV mass18). A recent study by van Woerden et al revealed higher
EAT volume in patients with HFpEF than in healthy controls19). Therefore, one can imagine that EAT
is also involved in the pathophysiology of HFpEF. In patients with HFpEF, endothelial inf lammationand oxidative stress induced by comorbidities, such as obesity, hypertension, diabetes mellitus, andchronic kidney disease, have recently been shown to drive myocardial dysfunction and remodeling10).
In patients with visceral obesity, excessive fat cells tend to cause muscular hypertrophy and become
dysfunctional due to surplus energy. Dysfunctional fat cells release pro-inf lammatory adipokines
into the bloodstream, possibly leading to chronic systemic inf lammation associated with arterial
stiffness, endothelial dysfunction in arterioles, and fibrosis, all of which have been implicated in thedevelopment of HFpEF20,21). Therefore, the new paradigm proposes that myocardial dysfunction andremodeling in HFpEF result from a series of bad f low caused by comorbidities, especially visceralobesity. This may explain a high EAT volume in patients with HFpEF although there was no
significant difference in EAT volume between the HFpEF and control groups in the present study.
Recently, Pugliese et al showed the opposite association of EAT with cardiometabolic profile,
haemodynamics and outcome in HF cohorts. In HFrEF, EAT accumulation is protective as ametabolic reservoir, therefore, EAT reduction is detrimental. In HFpEF, on the other hand, increased
EAT plays an adverse role to promote haemodynamic derangements and alter adipogenesis bysecretion of pro-inf lammatory adipokines. Recent evidences suggest that natriuretic peptides
activate lipolysis in adipose tissue in patients with HFrEF24). Consequently, increased BNP levels
may contribute to the decrease in EAT in patients with HFrEF. A difference between the physiologic
and pathophysiologic roles of EAT may ref lect a difference in mechanisms responsible for the
progression of cardiac dysfunction in patients with HFpEF and HFrEF. Such information on the
difference in EAT volumes between the HFrEF and HFpEF groups may have a novel clinicalimplication in the therapy of HF. EAT may be a potential target for therapies using nutrient supply
and drugs, such as glucagon peptide-like 1 analogs, sodium glucose transport 2 inhibitors, or ghrelin26),
to prevent the progression of HF. Further studies are needed to confirm the finding of this study.
This study has several limitations. First, due to the cross-sectional, retrospective nature of thisstudy, we could not explore the direct causal relationships between EAT, comorbidities, andmyocardial function and contractility. Therefore, it remains unclear whether EAT is a cause or aconsequence of these diseases or merely an innocent bystander. Second, RV diastolic function was nottaken into account in our study, although it may relate to EAT volume in patients with HF. Third, we
did not measure various biological and metabolic markers such as pro-inf lammatory adipokines andfree fatty acids. Despite advances in the treatment of HF, our understanding of the energy metabolicmechanisms limiting cardiac pump function remains incomplete. In the future, the energy
metabolism in the failing human heart needs to be elucidated. Finally, due to limited data in the
HFpEF and control groups, only our primary question and not any additional questions could beanswered.
In conclusion, this study demonstrated that HFrEF patients with RV dysfunction had less EAT
compared to HFpEF patients, and less amount of EAT was related to the severity of RV dysfunction
in HFrEF.

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Correlation between EAT and RV Dysfunction in HFrEF

Acknowledgements
All authors have no COI to declare regarding the present study.
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25. Haddad F, Doyle R, Murphy DJ, et al. Right ventricular function in cardiovascular disease, part Ⅱ:
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Osaka City Med. J. Vol. 68, 73-80, 2022

Association between Receiving Feedback on the Results ofan Automated Cognitive Function Test and Motivation for
Dementia-preventive Behavior
SATOSHI AKADA1), KENTARO UCHIDA2), JUMPEI MARUTA3), HIDEO KUROZUMI1),SATOSHI NOGI1), and KOKI INOUE1,4)
Department of Neuropsychiatry1), Osaka City University Graduate School of Medicine;
Department of Neuropsychiatry2), Osaka Metropolitan University Graduate School of Medicine;
Department of Psychiatry3), Osaka City Kosaiin Hospital; andCenter for Brain Science4), Osaka Metropolitan University Graduate School of Medicine

Abstract
Background
Receiving feedback on the results of cognitive function tests is an effective motivating factor for
producing dementia-preventive behavior, but the association between receiving feedback on the
results of automated cognitive function tests and motivation for dementia-preventive behavior isunclear. We investigated the association between receiving feedback on the results of the Cogstate
Brief Battery and motivation for dementia-preventive behavior.
Methods
The participants were community-dwelling older adults aged ≧65 years without a diagnosis ofdementia or mild cognitive impairment. They were divided into the Cogstate Brief Battery andcontrol groups.

They responded to a questionnaire twice, 3 months apart. We compare thepercentage of participants who were more motivated regarding dementia-preventive behavior
between the two groups. Multivariate logistic regression analysis was conducted on the association
between being in the Cogstate Brief Battery group and a stronger motivation.
Results
The study included 222 participants (105 in the Cogstate Brief Battery group and 117 in control
group). Being in the Cogstate Brief Battery group was significantly associated with a stronger
motivation for dementia-preventive behavior, even after adjusting for sex, age, education, and contact
with persons with dementia. Factors such as sex were not significantly associated with a stronger
motivation.
Conclusions
This study found that receiving feedback automatically on the results of the Cogstate Brief
Received August 24, 2022; accepted October 31, 2022.
Correspondence to: Satoshi Akada, MD.
Department of Neuropsychiatry, Osaka Metropolitan University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: i21973f@omu.ac.jp- 73 -

Akada et alBattery was significantly associated with a stronger motivation for improved dementia-preventive
behavior among community-dwelling older adults. This study may provide useful insights forinterventions targeting dementia prevention among community-dwelling older adults.
Key Words: ‌The Cogstate Brief Battery; Cognitive function test; Motivating factor;
Behavior change; Older adults.

Introduction
Japan is a hyper-aged society with a declining birthrate and an aging population. According to thereport by Ninomiya et al, 36.4 million people aged ≧65 years accounted for 29.1% of the total
population in 2021, and this figure is estimated to reach 35.3% by 2040. Dementia is a major mental
disorder among older adults, and its prevalence among those aged ≧65 years in Japan is estimated toreach 20.7% by 20401). Dementia can lead to a variety of mental, physical, and social health problems
that impair qualitative living. Inappropriate eating habits, lack of exercise, heavy alcohol
consumption, and smoking are reported to be associated with the onset of dementia2,3), and change inlifestyle involving diet and exercise is effective for preventing dementia. However, few people actuallytake action to prevent dementia, and Smith et al reported that less than 40% of people take action toforestall dementia4). Reports indicate that dementia-preventive behavior is associated with a higher
level of knowledge about dementia 5,6) and awareness of cognitive decline 7). Therefore, gaining
knowledge about dementia and receiving feedback on the results of cognitive function tests should be
effective in motivating behavior change for the prevention of dementia.
The usefulness of the Mini Mental State Examination (MMSE)8) and the Montreal Cognitive
Assessment (MoCA)9) as simple bedside tests for screening mild cognitive impairment and dementia
associated with Alzheimerʼs disease has been reported, but recently, automated cognitive function
tests have begun to be widely used10). Tools such as the Cognitive Assessment for Dementia, iPadversion 2 (CADi2)11) and MSP-110012), which is produced by Nihon Kohden Corp (Tokyo, Japan), havealso been developed for mass screening for the secondary prevention of dementia. Automated tools
can be self-administered without the need for a specialist; they also take less time and are easier toadminister than conventional cognitive function tests13). Among these, the Cogstate Brief Battery(CBB) has been shown to have validity as a cognitive function test14) and has been reported to beeffective in screening for mild cognitive impairment and dementia associated with Alzheimerʼsdisease15,16). However, the association between receiving feedback on the results of CBB and the
motivation for improved dementia-preventive behavior is unclear.
In this study, we investigated the association between receiving feedback on the results of CBB,
which is an automated cognitive function test, and motivation for behavior change regarding theprevention of dementia among community-dwelling older adults. We compared the CBB group, which
was administered CBB, received feedback automatically on the results, and was educated about
dementia based on materials on important lifestyle changes for preventing dementia, with the nonCBB group, which was only educated about dementia.

Methods
Participants
Our co-researcher, Akakabe Co., Ltd. (Osaka, Japan), who operates drugstores nationwide,
recruited participants for this study. Participants were recruited from January 2021 to May 2021
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Cognitive Function Test and Behavior Changeusing personal information already held by Akakabe Co., Ltd. in its membership system. Our target
participants were community-dwelling adults in Japan aged ≧65 years who had not been diagnosed
with dementia or mild cognitive impairment. The required number of participants was set at 200(100 in the CBB group and 100 in the non-CBB group) with a threshold response rate of 30%,
expected response rate of 50%, power of 80%, and alpha of 0.05 (two-sided). The proportion of
dropouts and ineligible participants was estimated at 50%, and 400 participants were required in thefirst step. Those who had been diagnosed with dementia or mild cognitive impairment or had visiteda medical institution for cognitive dysfunction were excluded. This study was approved by the EthicalCommittee of Osaka City University Graduate School of Medicine (approval number: 2020-238). This
study was conducted in accordance with the Declaration of Helsinki and its future amendments. All
participants were informed of the purpose and methods of the study, and they provided writtenconsent.
ProcedureIn the first step, 400 participants were randomly assigned to two groups (CBB and non-CBB
groups) by a simple method, with 200 participants in each group. After gaining prior consent for
mailing, CBB was mailed to the CBB group, and CBB was administered and the results were fed backautomatically to the participants. All participants were educated on dementia and important lifestylechanges for preventing dementia using relevant materials. In addition, a questionnaire was mailed
to all participants and their responses were obtained. For the CBB group, the questionnaire wasprovided before the CBB was administered. The questionnaire included five questions regarding sex,age, educational background, contact with dementia, and whether they were willing to change theirlifestyle to prevent dementia. For education, we calculated the number of years of education. We
defined “contact with dementia” as having a history of personal contact with people with dementia.
In the second step (3 months after the first step), a questionnaire was mailed to all participants
regarding whether they were willing to change lifestyle for the prevention of dementia, and their
responses were recorded. Concerning the questionnaire on whether they were willing to change theirlifestyle to prevent dementia, the respondents were asked to choose from five stages: “1: not planningto change within 6 months”, “2: planning to change within 6 months”, “3: planning to change within 1month”, and “4: have changed but for less than 6 months”, “5: have changed for more than 6 months”.
Because the dropout rate from the non-CBB group was higher than expected, 150 additional non-CBB
participants were added to this study, for a total of 550 participants who fully consented to the study.
The Cogstate Brief Battery
CBB which is produced by Cogstate, Ltd. (Melbourne, Australia) is an automated tool for cognitive
self-assessment and consists of four cognitive tests that assess psychomotor function, attention,
working memory, and visual learning17). CBB plays an important role in Alzheimerʼs disease researchand clinical trials18,19) and has been reported to be effective in screening for mild cognitive impairment
and dementia associated with Alzheimerʼs disease15,16). Furthermore, because CBB is a computerbased tool, the administration, evaluation, and reporting of the test is automated and highly
standardized. It can be administered in 10 minutes, making it easier to apply than conventional
cognitive function tests. In addition, as CBB is not a medical device, it can be easily used at eventsfor residents. In the US and Europe, CognigramTM, which is a medical version of CBB with a
specialized feedback function for medical professionals, has been approved as a medical device and isused to assist medical professionals in examining and diagnosing mild cognitive impairment and- 75 -

Akada et aldementia20,21). The nouKNOW, developed by Eisai Co., Ltd. in Japan, was used in this study. It is theJapanese version of CBB, and the content of the nouKNOW test is the same as that of CBB, withadditional advice on dementia prevention as feedback. The nouKNOW was developed as a digital tool
(non-medical device) for self-checking brain performance. The results of nouKNOW are fed back to
the participants with the Concentration score and the Memory score. These scores range from 0 to 50(0-14.9: incorporate activities to maintain and improve, 15-19.9: border line, 20-50: normal).
Furthermore, recommendations on lifestyle improvement such as habits of regular exercise, nonsmoking, balanced diet intake, and moderate alcohol consumption as well as on physical and mental
health management, such as on the management of blood pressure, blood sugar, body fat, mental
health, and hearing consumption related to the test results is automatically fed back to participants.
Statistical analysis
Statistical analysis was performed using EZR software (Saitama Medical Center, Jichi Medical
University, Saitama, Japan), which is a graphical user interface for R (version 2.13.0; R Foundationfor Statistical Computing, Vienna, Austria). We investigated the association between receiving
feedback on the results of CBB, which is an automated cognitive function test, and motivation for
dementia-preventive behavior. Regarding the questionnaire on whether they were willing to change
their lifestyle to prevent dementia, the respondents whose stage of behavior changed from “1” to “2”,“3”, “4”, or “5”, from “2” to “3”, “4”, or “5”, and from “3” to “4” or “5”, from the first to the second step,
were considered to be more motivated regarding dementia-preventive behavior; the rest wereconsidered to be less motivated. Age was compared using a studentʼs t-test. Sex and whether
participants had contacted people with dementia were compared using Fisherʼs exact test. Education
and whether participants were willing to change their lifestyle to prevent dementia was comparedusing the Mann-Whitney U test. After adjusting for factors such as sex, age, education, and contact
with dementia, multivariate logistic regression analysis was conducted on the association between
being in the CBB group and a stronger motivation for dementia-preventive behavior. Education4,7)
and contact with dementia 22-24) have been reported to be associated with dementia-preventive
behavior; therefore, they were set as confounding factors. Studentʼs t-test was used for intergroupcomparison of the Concentration and Memory scores between the group that is motivated towards
dementia-preventive behavior and the one that is not. P values ＜0.05 were considered statisticallysignificant.

Results
This study included 550 (200 in the CBB group and 350 in the non-CBB group) communitydwelling older adults. After excluding 30 persons who did not respond in the first step (8 in the CBBgroup and 22 in the non-CBB group), 203 persons who responded in the first step but not in thesecond step (46 in the CBB group and 157 in the non-CBB group), and 95 persons whose questionnaires
were invalid due to missing values (41 in the CBB group and 54 in the non-CBB group), 222participants (105 in the CBB group and 117 in the non-CBB group) were included in the analysis.
Table 1 shows the characteristics of the participants assigned to the CBB and non-CBB groups.
Significant differences were found in sex (p＝0.037), age (p＝0.004), and education (p＝0.049).
Table 2 shows the odds ratios (ORs) and 95% confidence intervals (CIs) for the multivariate
logistic regression analysis of the association between being in the CBB group and a stronger
motivation for dementia-preventive behavior, after adjusting for factors such as sex, age, education,- 76 -

Cognitive Function Test and Behavior Change

and contact with dementia. Being in the CBB group was significantly associated with a stronger
motivation for dementia-preventive behavior (OR＝1.99; CI: 1.10-3.61; p＝0.023). Sex, age, education,and contact with dementia were not significantly associated with a stronger motivation for dementiapreventive behavior.
Table 3 shows the association between the score of CBB and motivation for dementia-preventive
behavior. Significant differences were not found in both Concentration (p＝0.117) and Memory (p＝0.189) scores.

Table 1. Characteristics of the participants
CBB group

Non-CBB group

No
Yes
1

105
17 (16.2%)
88 (83.8%)
71.70±4.67
12 (9-16)
55 (52.4%)
50 (47.6%)
60

117
33 (28.2%)
84 (71.8%)
73.81±6.05
12 (9-16)
77 (65.8%)
40 (34.2%)
64

2
3
4
5
1

15
5
2
23
36

20
6
2
25
50

16
8
5
40
22.87±4.58

21
6
6
34

Results of CBB2
3
4
5
C-score(mean±SD)

M-score24.08±5.45nSexAge, years (mean±SD)
Education, years (range)
Contact with dementia
Question about change
in lifestyle † (first step)

Question about change
in lifestyle † (second step)

Men
Women

p-value
0.037
0.004
0.049
0.055
0.832

0.114

1: not planning to change within 6 months, 2: planning to change within 6 months, 3: planning to change within
1 month, 4: have changed but for less than 6 months, 5: have changed for more than 6 months. Abbreviations: CBB,
Cogstate Brief Battery; SD, standard deviation; C-score, Concentration score; and M-score, Memory score.
†

Table 2. Influencing factors for improved dementia-preventive behavior

Group
Sex
Age, years
Education, years
Contact with dementia

CBB
Non-CBB
Men
Women

No
Yes

All

N of participants withimproved dementiapreventive behavior

105
117
50
172

43 (41.0%)
32 (27.4%)
14 (28.0%)
61 (35.5%)

132
90

42 (31.8%)
33 (36.7%)

OR † (95% CI)

p-value

1.99 (1.10-3.61)

0.023

0.81 (0.39-1.69)

0.57

1.04 (0.99-1.10)
0.97 (0.84-1.12)
0.88 (0.48-1.59)

0.15
0.67
0.66

OR was adjusted for sex, age, education, and contact with dementia. Abbreviations: N, number; OR, odds ratio; CI,
confidence interval; and CBB, Cogstate Brief Battery.
†- 77 -

Akada et al
Table 3. Association between the scores of CBB and motivation towards dementia-preventive behaviornC-score (mean±SD)
M-score (mean±SD)

Motivated to change lifestyle

Not motivated to change lifestylep-value43
23.71±4.51

6222.29±4.57

0.117

23.24±5.63

24.66±5.28

0.189

Abbreviations: CBB, Cogstate Brief Battery; C-score, Concentration score; M-score, Memory score, and SD, standard
deviation.

Discussion
This study aimed to determine whether there is an association between receiving feedback on the
results of CBB, which is an automated cognitive function test, and motivation for dementia-preventive
behavior among community-dwelling older adults. The study found two things. First, receiving
feedback on results of CBB, not the score of CBB, was significantly associated with a stronger
motivation. Second, factors such as sex, age, education, and contact with dementia were notsignificantly associated with a stronger motivation. These results suggest that receiving feedback on
the results of CBB is effective in motivating community-dwelling older adults who have not been
diagnosed with dementia or mild cognitive impairment to change their lifestyles for the prevention ofdementia.
First, receiving feedback on the results of CBB motivated dementia-preventive behavior.
Prochaska et al. identified dramatic relief as one of the 10 processes (Consciousness raising,
Dramatic relief, Environmental reevaluation, Self-reevaluation, Self-liberation, Social liberation,
Contingency management, Helping relationship, Counterconditioning, and Stimulus control) that
produce behavior change25). Dramatic relief refers to the experience of various emotional reactions
and feelings that motivate behavior change, and in this study, learning about oneʼs own cognitive
functioning by receiving feedback on the results of CBB, and the resulting emotional reactions, suchas being happy or sad, were considered to fall under the category of dramatic relief. A report notedthat awareness of the importance of actions for preventing dementia was associated with actual
preventive actions26), and in this study, the combination with dramatic relief seemed more effective.
Among automated tools for self-checking cognitive function, CBB is sufficient to detect mild cognitive
impairment related to Alzheimerʼs disease associated with Alzheimerʼs disease15,16). Therefore, it isconsidered that no ceiling effect occurred and the test was able to provide appropriate feedback, evenwhen used for people who are generally considered cognitively normal, such as community-dwellingolder adults.
Second, factors such as sex, age, education, and contact with dementia were not significantly
associated with a stronger motivation for improved dementia-preventive behavior. Education4,7) andcontact with dementia22-24) have been reported to be associated with dementia-preventive behavior.
Although studies indicate that people who have contact with dementia are less likely to believe thatdementia is preventable27), in this study, contact with dementia was not a significant inhibitor of
motivation for dementia-preventive behavior. These results suggest that CBB-based interventions
are effective for a wide range of people with different backgrounds, and CBB may enable us to reachthose who are less likely to take action to prevent dementia.
There are several limitations to this study. First, there were significant differences in sex, age,and education between CBB and non-CBB groups. This may have been due to participation bias, as- 78 -

Cognitive Function Test and Behavior Change

those who cooperated in the study, which was more time-consuming than the non-CBB group,participated in the CBB group. However, even after adjusting for known factors that inf luencedementia-preventive behavior, such as sex, age, education, and contact with dementia, receiving
feedback on results of CBB was significantly associated with a stronger motivation for dementiapreventive behavior. Therefore, the bias in characteristics between CBB and non-CBB groups does
not seem to weaken our argument. Second, the dropout rate was high between the first and second
steps. Since many of the participants who dropped out were considered less likely to be motivated tochange their lifestyle for the prevention of dementia, it is possible that the proportion of participants
who became more motivated was actually higher than noted. However, the CBB group had a lower
dropout rate than the non-CBB group. Therefore, this does not weaken our argument that the CBBgroup was more motivated. Third, 6 months is the standard definition of each stage in the behavior
change stages proposed by Prochaska et al 25), but in this study, participants were asked in aquestionnaire about their willingness to change their lifestyle for the prevention of dementia 3months after the first step. Therefore, the long-term effects are not known. Fourth, although thisstudy showed an association between receiving feedback on CBB results and motivation for dementiapreventive behavior, we were unable to follow the progress after that point. Therefore, we do notknow whether the increased motivation actually led to the prevention of dementia. Future
longitudinal studies on the development of dementia after receiving feedback on the results of CBB
are awaited.
This study found that receiving feedback on results of CBB was significantly associated with astronger motivation for dementia-preventive behavior among community-dwelling older adults aged
≧65 years who were undiagnosed with dementia or mild cognitive impairment. This study should

provide useful insights regarding dementia prevention among community-dwelling older adults.
Acknowledgements
All authors have no COI to declare regarding the present study.
This study was conducted with the support of the Wellness Open Living Lab, which provided thenouKNOW and funds for this study, among other forms of support. We would like to thank Editage(https://www.editage.com) for the English language editing. The authors also acknowledge the role of
Akakabe Co., Ltd. in conducting this study. We would also like to express our sincere gratitude to theassociations in the target areas and to all the people who understood the purpose of this study andwillingly cooperated.
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16. Maruff P, Lim YY, Darby D, et al. Clinical utility of the cogstate brief battery in identifying cognitive
impairment in mild cognitive impairment and Alzheimerʼs disease. BMC Psychol 2013;1:30.
17. Fredrickson J, Maruff P, Woodward M, et al. Evaluation of the usability of a brief computerized cognitive
screening test in older people for epidemiological studies. Neuroepidemiology 2010;34:65-75.
18. Weiner MW, Veitch DP, Aisen PS, et al. The Alzheimerʼs Disease Neuroimaging Initiative 3: continued
innovation for clinical trial improvement. Alzheimers Dement 2017;13:561-571.
19. Mackin RS, Insel PS, Truran D, et al. Unsupervised online neuropsychological test performance for individuals
with mild cognitive impairment and dementia: results from the Brain Health Registry. Alzheimers Dement(Amst) 2018;10:573-582.
20. Stricker NH, Lundt ES, Albertson SM, et al. Diagnostic and prognostic accuracy of the Cogstate Brief Battery
and Auditory Verbal Learning Test in preclinical Alzheimerʼs disease and incident mild cognitive impairment:
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and prodromal AD (MCI A ＋ T ＋ ) in a population-based sample. Alzheimers Dement 2021;17:584-594.
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study among older adults participating in a prevention trial. BMC Geriatr 2020;20:99.
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Osaka City Med. J. Vol. 68, 81-90, 2022

A History of Obesity in Severe Anorexia Nervosa Predicts
Outpatient Treatment Dropout
MIHOKO HONDA1), TOMOKO HARADA2), TSUNEO YAMAUCHI2), SAORI MIYAMOTO2), TAKUMI MATSUZUKA1),
AKIHIRO MUI1), NAOKI OHARA1), and KOKI INOUE2)
Department of Neuropsychiatry1), Osaka City University Graduate School of Medicine; andDepartment of Neuropsychiatry2), Osaka Metropolitan University Graduate School of Medicine

Abstract
Background
Anorexia nervosa (AN) is a psychiatric disorder with a high mortality rate, and low body massindex (BMI), one of features of AN, is a poor prognostic factor. Treatment dropout is common in AN.
Treatment dropout is related to the AN binge-eating/purging subtype, low BMI, and age. The
relationship between a history of obesity or family involvement and treatment dropout is unknown.
We investigated the relationship between treatment dropout in outpatients with AN with low BMI
and a history of obesity or family involvement.
Methods
This retrospective study analyzed adult female patients with AN with BMI ＜16 kg/m2. Age and
BMI at the initial visit, marital status, AN subtype, maximum weight, a history of obesity, andaccompanying persons at the initial visit as a family involvement were assessed. Factors associatedwith treatment dropout from the initial visit to 6 months were examined.
Results
The 6-month dropout rate was 33.1% (57 dropped out, 115 continued treatment). Treatment
dropout was significantly associated with a history of obesity and low BMI at the initial visit.
Treatment dropout was not significantly associated with the presence or absence of family members
at the initial visit.
Conclusions
To prevent treatment dropout of physical high-risk patients with low BMI, clinicians need torecognize patients with a history of obesity and provide them with psychotherapy considering theirperceptions and stigmas of obesity.
Key Words: Anorexia nervosa; Treatment dropout; Obesity; Outpatient

Received September 1, 2022; accepted October 31, 2022.
Correspondence to: Tomoko Harada, MD, PhD.
Department of Neuropsychiatry, Osaka Metropolitan University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: t-harada@omu.ac.jp- 81 -

Honda et al

Introduction
Eating disorders (EDs) are psychiatric disorders characterized by abnormal eating behavior,
excessive valuing of weight and shape, and cognitive deficits1). Anorexia nervosa (AN) is an ED
characterized by low body weight and associated with high mortality2). Patients with AN are at highrisk of early mortality3), and factors that increase the risk of mortality in AN include low body massindex (BMI), long duration of disease, substance abuse, and poor psychosocial functioning 4,5). The
standardized mortality ratio for patients with AN was reported as 11.7 and that for patients with AN
with BMI less than 11.5 kg/m2 was over 306).
Dropout rates have been reported to be 31%-50% for inpatients and 23%-57% for outpatients7). As
studies on treatment dropout differ in treatment methods, definition of dropout, and observation
period, the dropout rates have been reported to range widely7,8). Treatment dropout had a severe
impact on recovery, and patients who dropped out from treatment early were less likely to recover on
their own and had a greater risk for relapse 9). In a 10-year prognostic study using cognitive
behavioral therapy (CBT), the treatment dropout group had a poorer prognosis than the treatmentcompletion group10). In particular, treatment dropout among patients with AN with low BMI is aserious problem because of the high risk of mortality. Factors affecting dropout need to be examined
to prevent treatment dropout. Previous studies have reported on various factors responsible fortreatment dropout in patients with AN in hospitalization and outpatient settings7,8). Predictors oftreatment dropout were reported to be the AN binge-eating/purging type (AN-BP), age, and BMI for
inpatient treatment11,12) and the AN-BP subtype, ED-related quality of life13), and anxiety level14) for
outpatient treatment.
The association between premorbid overweight or obesity and the development of EDs has been
established15,16). Patients with ED with a history of overweight or obesity have been reported to havea higher rate and speed of weight loss, higher physical risk17), and greater severity of psychopathology
related to EDs compared to patients with EDs without a history of obesity18). Therefore, patients with
AN with a history of obesity are likely to be at high risk of treatment dropout, but this is not clear.
It is also known that family involvement in AN treatment is effective in children andadolescents19). Some reports of adults with AN have examined the association between caregiverinterventions and patient treatment effects20,21), but to our knowledge, it is not clear whether family
involvement is related to the factors associated with treatment dropout in adults with AN. However,
it is assumed that even in adults with AN undergoing treatment, caregiver, i.e., family and partner,
cooperation and interest in treatment is associated with the continuation of patient visits to thehospital.
In this study, we examined the association between treatment dropout in the outpatient setting
and a history of obesity and family involvement in adult female patients with AN with severe, low
BMI.

Methods
Patients
This was a retrospective study based on the medical records of outpatients with AN who visitedthe Department of Neuropsychiatry at Osaka City University Hospital (now Osaka Metropolitan
University Hospital) between January 1, 2014, and November 31, 2021. This institution is a large
urban-type general hospital that provides specialized outpatient and inpatient treatment for patients- 82 -

Factors of Outpatient Dropout in Anorexia Nervosawith EDs. AN was diagnosed by psychiatrists with extensive clinical experience in ED based on the
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)22). This study included
patients with AN who were older than 18 years and had a BMI less than 16 kg/m2, classified as severe
and most severe based on the DSM-5 criteria. Patients who were aged less than 18 years or had a
BMI of 16 kg/m2 or higher were excluded. In addition, to investigate patient-initiated dropout, we
excluded patients who dropped out for the following reasons: dropout due to not consenting to thetreatment agreement at the initial visit, transferring to a different hospital, moving to a distant place,or pregnancy within 6 months from the initial visit. Those who received inpatient treatment within 6months of the initial visit were also excluded, as inpatient hospitalization is a factor associated withdropout or continued treatment. A total of 172 patients were included in the study.
Procedure
Variables collected included age of onset, duration of illness, AN subtype, i.e., AN restricting type
(AN-R) or AN-BP, career status, and marital status. We defined family involvement in treatment asfamily members accompanying the patients and collected data on accompanying persons at the initial
visit. We also collected information on the patientsʼ age, weight, height, and BMI at the time of theinitial visit, as well as their lifetime maximum weight, height, and age at that time.
Patients with or without a history of obesity were classified based on maximum weight. If thepatients were 18 years or older at their maximum weight, a BMI of 25 kg/m2 or more was considered
to indicate obesity according to the definition of the Japan Society for the Study of Obesity23). If thepatients were under 18 years of age at their maximum weight, we calculated the standard weight anddegree of obesity [degree of obesity＝{(actual weight−standard weight)/standard weight}] from theirage and height at that time, using the standard weight calculation formula of the Japanese Society
for Pediatric Endocrinology24), which was developed based on data from the 2000 Report of the School
Health Statistics Survey (5-17 years) by the Ministry of Education, Culture, Sports, Science andTechnology25). If the degree of obesity was greater than 20%, the patient was considered to have ahistory of obesity according to the definition of the Japanese Society for Pediatric Endocrinology24).
Patients who dropped out of treatment on their own within 6 months from the initial visit were
included in the “Dropout group” and those who continued treatment for more than 6 months from theinitial visit were included in the “Continuation group”. Censored patients who improved during the 6months and completed treatment were included in the continuation group. This study was approvedby the Ethics Committee of the Osaka City University Graduate School of Medicine (now Osaka
Metropolitan University Graduate School of Medicine) (approval number: 2020-106).
Statistics analysis
We compared the sociodemographic and clinical characteristics of patients between the dropout
and continuation groups using the chi-square test and the Mann-Whitney U-test. Kaplan-Meiersurvival analysis was performed to estimate the treatment continuation rate for the two groups
according to whether the patients had a history of obesity. We used multivariate Cox regression
analysis to calculate hazard ratios and 95% confidence intervals to examine factors associated withtreatment dropout from the initial visit to 6 months. Data were analyzed using SPSS 26 for Mac OS
X (SPSS Japan, Tokyo, Japan).

Results
The dropout group consisted of 57 patients, and the continuation group consisted of 115 patients.
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Honda et al

The dropout rate for outpatient treatment during the 6-month period was 33.1%. Table 1 shows acomparison of sociodemographic and clinical background data of the patients in the dropout andcontinuation groups. There was no significant difference in age at the initial visit, duration of illness,or age of onset between the groups. In the AN subtype, the rates of AN-R and AN-BP were 58.7% (n＝101) and 41.3% (n＝71), respectively. The proportion of patients with AN-BP was higher in the
dropout group (50.9%, 29/57) than in the continuation group (36.5%, 42/115), but the difference was
not significant. There was a significant difference in marital status (p＝0.015), with 28.1% (16/57) of
the patients in the dropout group and 19.1% (22/115) of the patients in the continuation group being
married. The presence or absence of accompanying persons at the initial visit and career status were
not significantly different between the groups.
Table 2 shows a comparison of BMI and presence or absence of a history of obesity between the
dropout and continuation groups. There were no significant differences in BMI at the initial visit,
maximum BMI, age at maximum weight, or a history of obesity between the groups.
The difference in treatment dropout between patients with and without a history of obesity isshown in Figure 1. The x-axis represents the number of days in the first 6 months of treatment, andthe y-axis corresponds to the percentage of patients who continued treatment. One patient was
censored because she improved and no longer required to go to the hospital. Although the dropout
rate tended to be higher in the group with a history of obesity, the log-rank test showed no significant
difference between patients with and without a history of obesity.
Factors associated with treatment dropout were analyzed using Cox regression analysis (Table 3).
Covariates included were a history of obesity and the presence of an accompanying person at theinitial visit, which were adjusted for previously reported treatment dropout factors including age, AN
subtype, and BMI at the initial visit. A history of obesity and low BMI were significantly associated

Table 1. C omparison of sociodemographics of patients at the initial visit between the dropout andcontinuation groups
Dropout（n＝57）

Continuation（n＝115）

median [interquartile range]age (years)
age of onset (years)
duration of illness (years)

type
marital statuscareer status

accompanying person

AN-R
AN-BP
unmarriedmarrieddivorce/bereavement
unemployedemployed
student
yesno32.6 [23.3-40.3]
19.9 [17.8-30.4]
5.1 [1.5-12.3]

25.7 [20.8-37.2]
19.7 [17.7-23.1]
3.7 [1.2-10.5]

nn

28 (49.1%)
29 (50.9%)
32 (56.1%)
16 (28.1%)
9 (15.8%)

73 (63.5%)
42 (36.5%)
87 (75.7%)
22 (19.1%)
6 (5.2%)38 (33.0%)
44 (38.3%)
33 (28.7%)
97 (84.3%)
18 (15.7%)

27 (47.4%)
18 (31.6%)
12 (21.0%)
43 (75.4%)
14 (24.6％ )

p
0.058
0.197
0.206

0.072
0.015

＊

0.183

0.158

statistically significant. AN-R, anorexia nervosa-restricting type; and AN-BP, anorexia nervosa binge-eating/purging type.
＊- 84 -

Factors of Outpatient Dropout in Anorexia Nervosawith dropout from outpatient treatment from the initial visit to 6 months. Age, AN subtype, and thepresence of an accompanying person at the initial visit were not significant predictors of treatment
dropout.

Table 2. Comparison of body mass index and a history of obesity between the dropout and continuationgroupsDropout（n＝57）

Continuation（n＝115）

median [interquartile range]p

BMI at the initial visit (kg/m2)

13.2 [11.7-14.7]

13.7 [12.6-14.7]

0.097

maximum BMI (kg/m2)

21.5 [19.8-23.8]
19.5 [16.8-21.9]

21.2 [19.3-23.0]
18.3 [16.7-22.3]

0.342
0.583

n

n

14
43

16
99

age at maximum weight (years)

history of obesity

yes
no

0.083

BMI, body mass index.

Table 3. Variables predicting dropout from anorexia nervosa outpatient treatment
Variables at the initial visit

HR

95% CI

p

age

1.012

0.989-1.036

0.307

type: AN-R
type: AN-BP
BMI

1
1.602
0.851

(Reference)
0.946-2.713
0.727-0.996

0.08
＊
0.045

history of obesity

1.989

1.062-3.727

0.032

accompanying person

0.696

0.368-1.318

0.266

＊

＊
statistically significant. HR, hazard ratio; CI, confidence interval; AN-R, anorexia nervosa-restrictive type; AN-BP,
anorexia nervosa binge-eating/purging type; and BMI, body mass index.

Figure 1. Cumulative survival rate of treatment dropout using the Kaplan-Meier method for patients with andwithout a history of obesity. One patient was censored because of improvement.

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Honda et al

Discussion
We found that a history of obesity and low BMI at the initial visit were associated with dropout
from outpatient treatment. The presence of an accompanying person at the initial visit was not
significantly associated with treatment dropout. Low BMI has been reported to be a risk factor forearly mortality3) and a poor prognostic factor26); thus, prevention of treatment dropout is necessary,
especially in outpatients with AN with low BMI. To the best of our knowledge, this was the firststudy to determine the relationship between a history of obesity and treatment dropout in female
outpatients with AN with low BMI.
A history of obesity was a significant factor for treatment dropout in our study. The dropout rates
tended to be higher among patients with a history of obesity, although the log-rank test showed nosignificant difference. When adjusted for factors previously reported to be associated with treatment
dropout including age, AN subtype, and BMI at the initial visit, the multivariate Cox regression
analysis showed that a history of obesity was significantly associated with treatment dropout. Body
dissatisfaction was stronger in individuals who were overweight or obese27-29), and stigma and body
dissatisfaction in these individuals were risk factors for EDs30-32). Patients with AN with a history ofobesity were shown to experience more weight-based teasing from peers and more frequent talks of
their weight from their families compared to patients with AN without a history of obesity33). In
addition, patients with AN with a history of obesity were also reported to have more severe ED
symptoms such as weight and shape concerns and higher degrees of anxiety and depression33).
Similar to the findings of previous reports, we assumed that the patients with AN with a history ofobesity in our study had harbored body dissatisfaction and weight-related stigma due touncomfortable comments regarding their weight in the past. They appeared to have also experienced
anxiety and depression, which may have prevented them from continuing to be motivated to seek
treatment. Furthermore, the difference between the adulthood maximum weight and current weight
was reported to be associated with overeating34,35) and with greater and faster weight gain in thetreatment of AN35). It appears that the patients with a history of obesity in this study were also more
likely to overeat and gain weight. As psychological improvement was shown to be slower than weightgain36,37), patients in this study are assumed to have dropped out of treatment because of increased
fear of obesity. Additionally, in our study, we used the Japanese criteria for obesity to consider thedifference in body size from Westerners, and the proportion of individuals with a history of obesity inthe total sample was 17.4%. Previous studies have indicated that lifetime obesity in patients with
EDs was 28.8% 18) and the rate of premorbid overweight or obese in patients with AN was
approximately 40%33,38). The proportions we reported were lower than those reported by previous
studies. This result is thought to be related to the lower BMI of Asians than that of Westerners39) andto the fact that there are fewer people with obesity in Japan40). In the Japanese culture where few
people are obese, the experience of obesity may have caused more intense distress.
We also found that low BMI at the initial visit was associated with treatment dropout. Low BMI
was similar to previous reports on dropout factors associated with inpatient treatment 11,12). It has
been suggested that patients with low weight have more severe psychopathology7), which might haveresulted in treatment dropout. In our study, the median BMI of the patients who dropped out was
12.9 kg/m2, which was considered low. It is especially important to strive to prevent patients withseverely low BMI from dropping out because these patients are exposed to the highest medical risk ifthey do not receive effective treatment5,6).
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Factors of Outpatient Dropout in Anorexia Nervosa

We considered accompanying persons at the initial visit as a representative factor of family
involvement in treatment. However, we found no significant difference between treatment dropout
and the presence or absence of accompanying persons at the initial visit to the hospital. Dysfunction
in a family with a patient with EDs was reported to related to worse ED psychopathology41), whichsuggesting that therapeutic family intervention could be needed. It was also found that family
members of patients with AN had a poor understanding of the disease, holding the patient responsible
for the disease and regarding the disease as an issue of food42). A study that investigated a skill
training intervention for caregivers during the treatment of inpatients with AN reported thatpatients in the intervention group had improved ED psychopathology and quality of life20). It is
assumed that encouraging family involvement in inpatient and outpatient treatment settings helps
families gain a better understanding of the disease, build trust between the patient and family
members, and prevent treatment dropout. The rate of accompanying persons present at the initial
visit was 75.4% in the dropout group and 84.3% in the continuation group. As is evident from thisdata, presence or absence of accompanying persons at the initial visit did not have any significant
effect on the treatment dropout. Patientʼs lack of motivation and desire for treatment appears to be a
predominant factor for treatment dropout rather than the inf luence of others, such as accompanying
the patient to the hospital or encouraging the patient to visit the hospital. There could be association
between the presence or absence of an accompanying person after the second visit and treatment
dropout, which could not be investigated in this study.
The AN-BP subtype was not associated with treatment dropout in our study. The results ofprevious studies assessing whether AN-BP was associated with treatment dropout were notconsistent, with some finding no association43-45) and others finding an association12,13,46). AN-BP wasstrongly associated with impulsivity47), and controlling impulsivity was more difficult in AN-BP thanin AN-R48). Impulsivity was suggested as a reason that AN-BP was associated with treatment
dropout12). Since our sample included patients with a low BMI, there may not have been suchdifferences between AN-R and AN-BP.
The dropout rate within 6 months from the initial visit was found to be 33.1%. Previous metaanalyses have reported dropout rates of 23%-57% for outpatient treatment7), and our findings were
within this range. In the Japanese healthcare system, the treatment of EDs is generally based on
patient education and supportive psychotherapy49). Institutions that can use specific treatment
techniques such as CBT and family-based treatment are limited. Yamada and Motoyama50) describedthat typical treatment for EDs in Japan is similar to specialist supportive clinical management(SSCM)51). Our unit provides treatment similar to SSCM once every few days to once every 2 weeks,
depending on the patientʼs condition. A study on outpatient psychotherapy for outpatients with AN
aged 17-40 years, which defined dropout as failure to attend at least 15 of 20 sessions over a 6-month
period, reported a 37.5% dropout rate43). Another study with a longer observation period reported a
50% dropout rate for patients with AN over 16 years of age who continued treatment with enhanced
CBT for 1 year52). The dropout rate in our study was comparable to that in the study with the sameobservation period. This indicates that our treatment was as effective as other treatments.
Although treatment dropout may be due to psychological factors such as unpreparedness forrecovery on the part of the patient and considered to be unavoidable to some extent, the high rate oftreatment dropout in a disease with high mortality, particularly for patients with low BMI, is aserious problem. For patients with AN, the therapist should be aware of whether or not the patient- 87 -

Honda et al

has experienced obesity in the past. If so, special attention should be paid. 1. Psychotherapy should
be provided after confirming the perceptions and stigma that the patient has regarding obesity. 2.
Patients should receive psychoeducation that overeating symptoms are likely to occur after treatment
begins and that the weight gain is a process of recovery. 3. The therapist should carefully monitor theweight progress.
There were several limitations to our study. First, the sample size was small. If the sample size
had been larger, some results might have been statistically significant. Second, although each patient
had different backgrounds, such as the circumstances leading to the visit to our hospital and thehistory of treatment for eating disorders, we did not assess these factors, which possibly created aselection bias in the patients. Third, self-reports by patients of their maximum weight and height atthat time may have introduced recall bias. The World Health Organization definition53) of obesity is a
BMI of 30 kg/m2 or higher, but this study used a BMI of 25 kg/m2 or higher as defined by the Japan
Society for the Study of Obesity23); therefore, BMI values cannot be simply compared with those inprevious studies. Fourth, we could not follow up continuously on the presence or absence of an
accompanying person, which was noted only at the time of the initial visit, and we could not conduct aqualitative study on their involvement in the treatment. Finally, our study is limited in its
generalizability because it was conducted at a single institution, a university hospital with a highlevel of functionality.
In conclusion, factors contributing to treatment dropout in outpatients with AN were investigatedin this study. We found that a history of obesity and low BMI were associated with treatment dropout
among patients with AN with severe low BMI. Recognizing and addressing a history of obesity may
improve treatment continuation rates for patients with AN with low BMI. An association between
family members accompanying the patient to outpatient treatment and treatment dropout was notapparent; further research is needed.
Acknowledgements
All authors have no COI to declare regarding the present study.
We are grateful to the professors of the Department of Medical Statistics at Osaka Metropolitan
University Graduate School of Medicine for their guidance and encouragement.
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go.jp/b_menu/toukei/001/h12/002.htm (In Japanese)
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study. Psychol Med 2001;31:881-890.
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29. Weinberger NA, Kersting A, Riedel-Heller SG, et al. Body dissatisfaction in individuals with obesity compared
to normal-weight individuals: a systematic review and meta-analysis. Obes Facts 2016;9:424-441.
30. Stice E. Risk and maintenance factors for eating pathology: a meta-analytic review. Psychol Bull 2002;128:825848.
31. Almeida L, Savoy S, Boxer P. The role of weight stigmatization in cumulative risk for binge eating. J Clin
Psychol 2011;67:278-292.
32. Gerke CK, Mazzeo SE, Stern M, et al. The stress process and eating pathology among racially diverse
adolescents seeking treatment for obesity. J Pediatr Psychol 2013;38:785-793.
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content/000711007.pdf (In Japanese)
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Osaka City Med. J. Vol. 68, 91-98, 2022

Strangulated Small-bowel Obstruction due toTransmesosigmoid Hernia Diagnosed with Multidetector Computed
Tomography: A Case Report
TOHRU TAKESHITA1), HISAKAZU MATSUSHIMA1), KIMIMASA IKEDA2), TOSHIKI NOMA2),TAKUYA GOTO1), and DAIJU UEDA3)
Departments of Radiology1) and Gastrointestinal Surgery2),
Osaka Habikino Medical Center; andDepartment of Diagnostic and Interventional Radiology3),
Graduate School of Medicine, Osaka Metropolitan University

Abstract

Transmesosigmoid hernia (TMSH), an emergency abdominal condition, is a type of internal hernia(IH) that involves the sigmoid mesocolon; its clinical symptoms are non-specific, so clinically its
preoperative diagnosis is usually difficult. Here, we report a case of TMSH in which multidetector
computed tomography (MDCT) clearly showed penetration of the small-bowel with its mesenteric fat
tissue and mesenteric vessels through a complete defect in the sigmoid mesocolon. These MDCT
findings accurately ref lected the direct findings of this rare type of IH, so we were confident in the
preoperative diagnosis.
Key Words: ‌Internal hernia; Transmesosigmoid hernia; Sigmoid mesocolon; Smallbowel obstruction; Multidetector computed tomography

Introduction
Internal hernia (IH) is a rare cause of small-bowel obstruction (SBO), accounting for ≦ 5.8% of allcases of SBO1). IHs involving the sigmoid mesocolon account for approximately 6% of all IHs1).
Transmesosigmoid hernia (TMSH) is a type of IH involving the sigmoid mesocolon2). A typical case of
TMSH is a middle-aged man or woman in his or her 50s to 60s with no history of abdominal surgery
and presenting with symptoms such as abdominal pain, abdominal distension, nausea, andvomiting 3-7). Because its clinical symptoms are non-specific, its clinical diagnosis is generally
difficult3-7). Currently, multidetector computed tomography (MDCT) has a central role in imaging
diagnosis of IH8). However, the computed tomography (CT) findings of TMSH have been reported only
in a few cases in the radiologic literature 4,5). Here, we report a case of TMSH in which correct
preoperative diagnosis was based on MDCT findings, which were confirmed by surgery.

Received April 11, 2022; accepted October 31, 2022.
Correspondence to: Tohru Takeshita, MD.
Department of Radiology, Osaka Habikino Medical Center,
3-7-1 Habikino, Habikino, Osaka 583-8588, Japan.
Tel: +81-072-957-2121; Fax: +81-072-958-3291
E-mail: ttakeshita@ra.opho.jp- 91 -

Takeshita et al

Case Report
A 79-year-old woman with a history of appendectomy due to appendicitis in her 50s presented tothe emergency room of our hospital with acute abdominal pain and nausea. She had been diagnosed
with a squamous cell carcinoma of the uterine cervix, T3bN1M0, FIGO stage Ⅲ C1, according to theTNM classification and the FIGO system9,10), at the age of 75 years. Consequently, she had beentreated with external-beam radiation therapy with concurrent chemotherapy and brachytherapy. A
follow-up examination at 42 months after the therapy revealed no evidence of locoregional recurrenceor distant metastasis. Physical examination revealed tenderness in the left-lower quadrant. Bloodtesting findings (Table 1) were within normal limits except for a slightly increased white blood cellcount (8800/μL) and elevated C-reactive protein level (17.01 mg/dL). An upright roentgenogram of
the abdomen showed several dilated small-bowel loops with air-f luid levels (Fig. 1). The attending
physician initially diagnosed an adhesive SBO and she was managed conservatively by the use of along intestinal tube. After 5 days of conservative therapy, her clinical condition remained unchanged.
Enterography with water-soluble iodinated contrast medium administered through the long intestinal

Figure 1. Abdominal roentgenogram showing several dilated small-bowel loops with air-f luid levels.

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Small-bowel Obstruction due to Transmesosigmoid Hernia
Table 1. Laboratory data on admission【CBC】【Biochemical】

WBC
RBC

8,800/μL
4.64×106/μL

ALB
T-BIL

4.5 g/dL
1.4 mg/dL

Hb
Ht
PLT

14.4 g/dL
40.9%
20.3×104/μL

BUN
CRE
Na
K
CL
AST
ALT
LDH
CK
AMY
CRP

20 mg/dL
1.17 mg/dL
138 mEq/L
4.0 mEq/L
100 mEq/L
30 U/L
18 U/L275 U/L
104 U/L
53 U/L
17.01 mg/dL

Figure 2. Enterography showing abrupt narrowing of the small-bowel at the upper-left pelvis level (white arrow).
The contrast medium passed through the stricture site and slowly f lowed into the small-bowel on the anal side (blackarrow).

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Takeshita et al

tube showed abrupt narrowing of the small-bowel in the left-upper pelvis. The contrast medium
passed through the stricture site and slowly f lowed into the small-bowel on the anal side (Fig. 2).
Contrast-enhanced MDCT of the abdomen and pelvis was performed as further investigation. Axial
MDCT images (Fig. 3) showed a f luid-filled, dilated, C-shaped small-bowel loop in the lower part of

Figure 3. A) Drawing showing the strangulated small-bowel obstruction (SBO) due to transmesosigmoid hernia in
our case. The horizontal lines B, C, and D correspond to subfigures B), C), and D) of the axial multidetector computed
tomography (MDCT) images, respectively.
B) Contrast-enhanced axial MDCT image through the just proximal to the hernia gate in the sigmoid mesocolon. This
axial MDCT image shows the afferent loop and efferent loop of the small-bowel and their mesenteric vessels are very
close to each other and converge toward the hernia gate (yellow dot circle). Note that the sigmoid vessels and superior
rectal vessels running along the margins of the hernia gate.
C) Contrast-enhanced axial MDCT image obtained at a 6-mm level caudal to B. This axial MDCT image is just distal
to the hernia gate and shows a f luid-filled and dilated herniated small-bowel loop (white asterisks) and convergence
toward the hernia gate (black arrowheads). Note that the sigmoid vessels and superior rectal vessels running along
the margins of the hernia gate. Note also that displacement of the sigmoid colon anteriorly by the herniated smallbowel loop.
D) Contrast-enhanced axial MDCT image obtained at an 8-mm level caudal to C. This axial MDCT image shows a
f luid-filled and dilated herniated small-bowel loop (white asterisks). Note the displacement of the sigmoid colon
anteriorly and medially by the herniated dilated small-bowel loop. Note also the thickened intestinal wall of thedilated small-bowel loop and poor contrast enhancement of the intestinal wall. These findings suggest strangulation.
S＝sigmoid colon, SV＝sigmoid vessels, SRV＝superior rectal vessels, PM＝left psoas muscle, GV＝left gonadal vessels,
EIA＝left external iliac artery, and IIA＝left internal iliac artery.

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Small-bowel Obstruction due to Transmesosigmoid Hernia

Figure 4. A) Drawing again showing the strangulated small-bowel obstruction (SBO) due to transmesosigmoid hernia
in our case. The vertical lines B, C, and D correspond to subfigures B), C), and D) of the sagittal multidetector computed
tomography (MDCT) images, respectively.
B) Contrast-enhanced sagittal MDCT image through the hernia gate in the sigmoid mesocolon.
C) Contrast-enhanced sagittal MDCT image obtained at a 2-mm level lateral to B.
D) Contrast-enhanced sagittal MDCT image obtained at a 4-mm level lateral to C.
These sagittal MDCT images clearly show the penetration of the small-bowel and its mesenteric fat tissue andmesenteric vessels through the defect in the sigmoid mesocolon (yellow arrows). Note that the sigmoid mesocolon(white arrowheads) is depicted as a thin sheet-like structure showing fat density and containing the sigmoid vessels.
Also note the herniated small-bowel (white asterisks) tapers and narrows appearing like a birdʼs beak toward thehernia gate in the sigmoid mesocolon.
S＝sigmoid colon, SV＝sigmoid vessels, and B＝urinary bladder.

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Takeshita et al

Figure 5. Selective volume-rendering three-dimensional computed tomography angiography image showing themesenteric vessel of the herniated small-bowel running an abnormal course (yellow arrows). Notice that themesenteric vessel of the herniated small-bowel runs dorsal to the sigmoid vessels.
AO＝abdominal aorta, SMA＝superior mesenteric artery, IMA＝inferior mesenteric artery, LCA＝left colic artery, SA＝sigmoid artery, and SRA＝superior rectal artery.

the pelvic cavity. Both ends of the C-shaped dilated small-bowel loop tapered toward the sigmoid
mesocolon. Each transitional point of the afferent loop and efferent loop of the small-bowel wereidentified and very close together. This finding suggested a closed-loop SBO. The sigmoid colon wasdisplaced anteriorly and medially by the C-shaped dilated small-bowel loop. In addition, a thickened
intestinal wall of the dilated small-bowel loop, poor contrast enhancement of the intestinal wall, andmesenteric haziness were observed, which strongly suggested a strangulated SBO. The location of
the obstruction site and its relationship with the surrounding structures suggested that the hernia
gate was located in the sigmoid mesocolon and that the small intestine had penetrated the defect inthe sigmoid mesocolon from cranial to caudal, thereby resulting in a strangulated SBO (i.e., astrangulated SBO due to TMSH, which is a type of IH). By combining the sagittal MDCT images(Fig. 4) with the volume-rendering three-dimensional CT angiography (3D-CTA) image (Fig. 5), theanatomical relationship of the sigmoid mesocolon, herniated small-bowel loop, and their mesentericvessels could be better understood, and the diagnosis of TMSH could be made more efficiently. The
patient underwent an emergency laparotomy. At surgery, a TMSH was confirmed. A small-bowel- 96 -

Small-bowel Obstruction due to Transmesosigmoid Hernia

segment, approximately 20-cm long and 60-cm distal to the ligament of Treitz was herniating througha complete defect in the sigmoid mesocolon. The incarcerated small-bowel was pulled out by gentle
traction. The incarcerated small-bowel was severely discolored and did not return to its normal color.
Thus, the necrotic segment of the small-bowel was resected, and end-to-end anastomosis was
performed. The defect of the sigmoid mesocolon was closed by suture. The patientʼs postoperative
course was uneventful. She was discharged on 09th hospital day after the operation.

Discussion
In 1964, Benson and Killen classified IHs involving the sigmoid mesocolon into three types:
intersigmoid hernia, TMSH, and intramesosigmoid hernia2). TMSH is defined as herniation of theviscus (mostly the small intestine) through a full-thickness defect in the sigmoid mesocolon. The
herniated small intestine passes through the hernia gate in the sigmoid mesocolon without having ahernia sac2). The etiology of the defect of the sigmoid mesocolon in TMSH is considered congenital or
acquired (such as prior abdominal surgery, blunt trauma, and peritoneal inf lammation)3-7).
Since the report by Benson and Killen2), nearly 20 cases of TMSH have been reported in the
English literature3-7). Patients with TMSH present with non-specific abdominal symptoms, making its
preoperative diagnosis usually difficult 3-7). Recently, the utility of MDCT for the preoperative
diagnosis of various types of IH has been apparent8). However, there are few reports showing the CT
appearance of TMSH. In 2004, Yu CY et al reported a case of TMSH in which the preoperative
diagnosis only was based on axial images on conventional CT4). Yu CY et al reported CT findings of
TMSH as follows4): (1) closed-loop SBO, (2) a cluster of f luid-filled dilated small-bowel loops located in
the left-upper pelvic cavity, (3) convergence of a herniated small-bowel toward the sigmoid mesocolon,
and (4) displacement of the sigmoid colon anteriorly and medially caused by the herniated smallbowel. These findings were also identified in the present case except for the location of the herniatedsmall-bowel. The location of a herniated small-bowel may depend on the direction of the herniation
and/or the length of a herniated small-bowel. In 2020, Francis KC et al proposed the omega sign as a
new CT sign for TMSH based on their case5). They stated that the omega sign was caused by anadhesive band between the surface of the sigmoid mesocolon and the pelvic sidewall, which caused
the sigmoid colon to resemble the English letter omega. However, that omega sign does not represent
a direct CT finding of TMSH, and it was not observed in our case. We believe that it is not a universal
CT finding but rather a coincidental finding produced by the effect of the adhesive band between thesurface of the sigmoid mesocolon and pelvic sidewall.
In the CT diagnosis of IH involving the sigmoid mesocolon, it is important to clarify the anatomical
relationship between the hernia gate and mesenteric vessels of the sigmoid mesocolon8). On CT, both
sigmoid vessels and superior rectal vessels are landmarks of the sigmoid mesocolon, and theattachment of the sigmoid mesocolon is close to both the left psoas muscle and left iliac vessels11). The
most impressive findings on CT in our case were that combined sagittal MDCT images and 3D-CTA
image could clearly visualize the small-bowel herniation with its mesenteric fat tissue and mesentericvessels passing through the defect in the sigmoid mesocolon. These CT findings well ref lected thepathophysiology of this rare type of IH, and we could make a preoperative diagnosis in confidence. To
the best of our knowledge, this is the first case in which the preoperative diagnosis of TMSH wasmade by combining sagittal MDCT images and 3D-CTA image from MDCT data.
In an emergency setting, the radiologic aim is not simply to diagnose SBO caused by IH but- 97 -

Takeshita et alimportantly, to then estimate the presence of intestinal and mesenteric ischemic changes associatedwith the SBO. It is worth noting that nearly half of the cases of TMSH have required resection of theherniated small-bowel3-7). Timely preoperative diagnosis and early surgical treatment will prevent
extensive and irreparable damage to the small-bowel and reduce the rate of mortality associated witha strangulated SBO caused by IH.
In conclusion, we encountered a case of strangulated SBO due to TMSH. This case highlights theutility of MDCT for diagnosis of this rare type of IH. Detailed knowledge of the anatomy of thesigmoid mesocolon is the key to the diagnosis of TMSH.
Acknowledgement
All authors have no COI to declare regarding the present case report.
Written informed consent was obtained from the patient for publication of this case report andany accompanying images.
We thank Kentaro Nishimura and Shinichi Uga, Radiological Technologists (Department ofRadiology, Osaka Habikino Medical Center) for preparing the MDCT images.
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Editorial Committee

Daisuke Tsuruta, MD (Chief Editor)
Yasuhiro Fujiwara, MD

Wakaba Fukushima, MD

Takeo Goto, MD

Yoshikazu Hiura, MD

Masayuki Hosoi, MD

Kazuo Ikeda, MD

Koki Inoue, MD

Yukio Miki, MD

Masahiko Ohsawa, MD

Atsushi Shioi, MD

Toshiyuki Sumi, MD

Kishiko Sunami, MD

Junji Uchida, MD

The volumes and issues published in 1954-2018 were as follows: Vol 1 (one issue), Vols 2-5 (2issues, each), Vols 6-7 (one issue, each), Vols 8-9 (2 issues, each), Vol 10 (one issue), Vol 11 (2issues), Vol 12 (one issue), Vol 13 (2 issues), Vols 14-20 (one issue, each), Vol 21 (2 issues), Vol 22(one issue), Vols 23-65 (2 issues, each), Vol 66 (one issue), Vol 67-68 (2 issues)

Publisher : Osaka City Medical Association,
Graduate School of Medicine, Osaka Metropolitan University
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan