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Right Ventricular Involvement and Outcome in Cardiac Sarcoidosis: Multimodality Imaging Findings

Noor Kareem Khalaf Albakaa 筑波大学 DOI:10.15068/0002008049

2023.09.04

概要

筑

波大

学

博士（医学）学位論文

Right Ventricular Involvement and Outcome in Cardiac
Sarcoidosis: Multimodality Imaging Findings

(心サルコイドーシスにおける右室病変と予後との関
連：マルチモダリティイメージング解析による検討)

2022
筑波大学大学院博士課程人間総合科学研究科
Noor Kareem Khalaf Albakaa

参考論⽂

心サルコイドーシス症例における右室長軸方向ストレインと心血管イベ
ントとの関連
This thesis is based on the following original article (Association between Right Ventricular
Longitudinal Strain and Cardiovascular Events in Patients with Cardiac Sarcoidosis).
Noor K. Albakaa, MD, Kimi Sato, MD, PhD, Noriko Iida, RDCS, PhD, Masayoshi Yamamoto,
MD, PhD, Tomoko Machino-Ohtsuka, MD, PhD, Tomoko Ishizu, MD, PhD, and Masaki Ieda,
MD, PhD. Published in Journal of Cardiology. Doi.org/10.1016/j.jjcc.2022.07.015.

Table of Contents
1- Cover

1

2- Information about the Published Paper

2

3- Table of Contents

4

4- List of Abbreviation

6

5- Background

7

5.1 Clinical Manifestation of Cardiac Sarcoidosis

7

5.2 Diagnosis and Treatment of Cardiac Sarcoidosis

6

5.3 Outcome of Cardiac Sarcoidosis

8

5.4 Right Ventricular Functional Assessment by the Conventional

9

Echocardiographic Parameters
5.5 Right Ventricular Functional Assessment by the Right Ventricular Free

9

Wall Strain (RVFWLS)
6- Purpose

12

7- Method
7.1 Study Population

13

7.2 Conventional Echocardiographic Parameters

13

7.3 Two-Dimensional Strain Analysis

14

7.4 FDG-PET Imaging Analysis

15

7.5 Cardiac Magnetic Resonance Imaging (CMR) Analysis

15

7.6 Electrophysiological Evaluation During Catheter Ablation

15

7.7 Statistical Analysis

16

8- Result

17

8.1Patient Characteristics

17

8.2 Clinical Outcome

17

8.3 Changes in RV Parameters during Steroid Therapy

19

8.4 Imaging Characteristics of Patients with Right Ventricular Dysfunction

19

8.5 FDG-PET and CMR Findings in Patients with Impaired RVFWLS

20

8.6 Electrophysiological Evaluation During Catheter Ablation

20

9- Discussion

21

9.1 Clinical Implication of RVFWLS in Cardiac Sarcoidosis

21

9.2 Right Ventricular Dysfunction in Cardiac Sarcoidosis

22

9.3 The Impact of Left Ventricular Involvement on Outcome

22

9.4 Limitations

23
4

10- Conclusion

24

11- Summary figure

25

12- References

26

13- Acknowledgements

30

14- Tables

31

15- Figures

46

5

4-List of Abbreviations
ACE, angiotensin-converting enzyme.
ACEI, angiotensin-converting enzyme inhibitor.
ARB, angiotensin II receptor blocker.
BNP, brain natriuretic peptide.
CS; cardiac sarcoidosis.
CMR, cardiac magnetic resonance imaging.
ECG, electrocardiogram.
FAC, fractional area change.
FDG-PET, 18F-fluorodeoxyglucose positron emission tomography.
GLS, global longitudinal strain.
IVS, interventricular septum.
JCS, Japanese circulation society.
LGE, late gadolinium enhancement.
LAVi, left atrial volume index.
LVEDVi, left ventricular end-diastolic volume index.
LVEF, left ventricular ejection fraction.
LV, left ventricular.
LVMi, left ventricular mass index.
LVESVi, left ventricular end-systolic volume index.
MR, mitral regurgitation.
NYHA, New York Heart Association.
RV, right ventricle.
RVD, right ventricular dysfunction.
RVFWLS, right ventricular free wall longitudinal strain.
sIL-2R, soluble interleukin-2 receptor.
SPECT, single-photon emission computed tomography.
S’, tricuspid lateral annular systolic velocity on tissue Doppler imaging.
TAPSE, tricuspid annular plane systolic excursion.
TR, tricuspid regurgitation.

6

5- Background
5.1 Clinical Manifestations of Cardiac Sarcoidosis
Sarcoidosis is a multisystemic disease of unknown etiology that most commonly affects the
lung, skin, heart, eye, and central nervous system. It is characterized by non-caseating
epithelioid granulomatous infiltration. In Japan the sarcoidosis prevalence is 7.5 to 9.3 per
100,000 persons, and the yearly incidence is 1 per 100,000 persons [1]. Approximately 25% of
patients with systemic sarcoidosis have cardiac involvement. Cardiac sarcoidosis (CS) is the
leading cause of morbidity and mortality in sarcoidosis patients [1-3].
The manifestations of CS depend on the size and the location of the granulomatous
infiltration. The presence of a small area of infiltration can be asymptomatic and only
diagnosed by routine health checkups. At the same time, granulomatous infiltration to cardiac
ventricles might cause thinning or aneurysm, which might lead to ventricular arrhythmias. One
of the common sites for infiltration is the basal interventricular septum (IVS). Thinning of the
basal part of the IVS is a specific sign of CS and is associated with the atrioventricular block
(AVB) and a high risk of cardiac events [1-4]. CS can cause localized or generalized wall
motion abnormality. While involved, a large area of left ventricle (LV) and right ventricle (RV)
causes heart failure symptoms [1-3]. Valvular regurgitation is also observed in CS. It could be
either due to the dilatation of the ventricle, which leads to valvular annulus dilatation, or direct
infiltration of the papillary muscle [1,5]. Patients with CS may be presented with AVB, atrial
or ventricular arrhythmia, or any ECG abnormality, which developed due to the infiltration of
the conduction system or myocardium, or it can be due to the dilatation of the cardiac chamber
[1-3]. In general, CS could be presented with different manifestations, which make its diagnosis
difficult.
5.2 Diagnosis and treatment of cardiac sarcoidosis
Systemic sarcoidosis is the involvement of at least two organs (including the lymph node).
Diagnosis of sarcoidosis is confirmed either by the presence of the non-caseating
granulomatous infiltration or the presence of a specific finding in the affected organ. Patients
with sarcoidosis should have periodic checking to determine early cardiac involvement [1,3].
Diagnosis of CS is challenging as it might mimic other cardiac conditions such as dilated
cardiomyopathy,

cardiac

hypertrophy,

chronic

myocarditis,

right

arrhythmogenic

cardiomyopathy, and ischemic heart disease [1-3]. The most specific test for CS diagnosis is
an endomyocardial biopsy (EMB) (Figure 1); however, it has low sensitivity due to the patchy
nature of the granulomatous infiltration [1,3].
7

The Japanese Circulation Society (JCS) guidelines for diagnosing and treating CS (2016)
set clinical, imaging, and histological criteria to diagnose CS [1]. In JCS guidelines, the criteria
for CS diagnosis are categorized into major criteria, which include (high-grade atrioventricular
block, ventricular arrhythmias, thinning of the basal interventricular septum, left ventricular
ejection fraction (LV EF) <50%, or regional wall motion abnormality, abnormal cardiac
accumulation on Ga citrate scintigraphy of FDG-PET and late gadolinium enhancement (LGE)
on CMR, and minor criteria which include abnormal ECG findings: ventricular arrhythmias
(non-sustained VT, multifocal or frequent PVC), bundle branch block, axis deviation, or
abnormal Q waves, perfusion defects on myocardial perfusion scintigraphy (SPECT), EMB
with monocyte infiltration and moderate or severe myocardial interstitial fibrosis. To fulfill the
CS diagnosis, two or more from the major or one from the major and two or more from the
minor are required to diagnose CS with systemic sarcoidosis, while for isolated CS, at least
four major criteria, including positive FDG uptake and one of the minor criteria [1].
Patients with active CS are treated with steroids as first-line therapy for inflammation
suppression [1,6]; however, for intractable cases or when there is a contraindication for using
steroids, other immune suppressive drugs (methotrexate, azathioprine, cyclophosphamide, etc.).
Further treatment is required according to the patient's condition as heart failure, arrhythmias,
and non-pharmacological treatment, which includes cardiac device implantation (pacemaker,
intracardiac defibrillator, cardiac resynchronization therapy), catheter ablation, surgical
treatment, and heart transplant [1].
5.3 Outcome of Cardiac Sarcoidosis
Historical series suggested a 5-year survival rate of 60% in patients with CS [7]. However,
contemporary data showed 5-year survival as 96%, indicating the improvement of their
survival with the appropriate use of anti-inflammatory medications, antiarrhythmic medication,
and device implantation [8].
While the general outcome in CS has been improved, several prior data showed that severe
LV dysfunction due to advanced sarcoidosis involvement in LV was associated with an
increased risk of death or ventricular arrhythmia and poor recovery on LV systolic function by
steroid therapy [1,7]. Other study also showed that RV involvement detected by CMR was
independently associated with cardiac events, mainly ventricular arrhythmia [9]. Because the
electrophysiological studies showed that the arrhythmogenic substrate in CS patients with
ventricular tachycardia was mainly in RV [10], detecting RV involvement may provide
additive information in detecting high risk patients in CS population.
8

Although, most of the CS patients have predominant LV disease and the extent of RV
involvement was associated with the severity of LV involvement [11], it has been observed
that up to 90% of the patients who had confirmed CS by either autopsy or by histological
examination after the heart transplant had RV involvement [12], RV involvement was also
observed by CMR [9,11,13,14]. Furthermore, few prior reports have highlighted the patients
presented with RV predominant symptoms or isolated RV involvement [15]. Since there was
a paucity of data if RV dysfunction sorely reflects the extent of LV damage by CS, detecting
RV dysfunction in CS may help us to detect patients with predominant RV disease and higher
risk of arrhythmic events.
Moreover, in recent decades there has been growing interest in studying the RV involvement
and dysfunction in many cardiac diseases, especially with the advancement in imaging
techniques. ...

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参考文献

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13- Acknowledgments

I would like to express my thanks and gratitude to Professor Masaki Ieda for giving me this

chance to do research and training in the cardiology department and for his support. My

appreciation and thanks to the inspiring teacher, Dr. Tomoko Ishizu, for her supervision and

support. Special thanks and gratefulness to Dr. Kimi Sato for her advice, effort, and time in

mentoring my research through the Ph.D. program. My thanks to all cardiology staff that I

learned from them directly or indirectly. All thanks to cardiology sonographers, whom I

learned a lot, and for being friendly and encouraging, especially (Dr. Norika Iida, Dr. Hideki

Nakajima, and Mr. Hiroyuki Naito), who let me enjoy learning and enlighten my journey.

My deep thanks and respect to the kind-heart patients in Tsukuba University Hospital; without

them, I couldn’t learn and do research.

Finally, I would like to acknowledge my thanks to my loving family, my parents, siblings, my

husband (Qasim), and my daughter (Zahraa) for their continuous support and love that keep

me going and cheer my life.

14.Tables

Table 1. Patient characteristics at baseline according to events.

Entire

Event

No event

cohort

n=11

n=40

n=51

(22%)

(78%)

Age, years

63±11

65±9

63±11

0.45

Sex, female, n (%)

31 (61)

7 (64)

24 (60)

0.83

1.60±0.20

1.60±0.21

0.93

NYHA functional class III/IV, n (%)

3 (6)

1 (9)

2 (5)

0.61

Diabetes mellitus, n (%)

6 (12)

6 (15)

0.17

Chronic lung disease, n (%)

5 (10)

1 (9)

4 (10)

0.93

Heart failure, n (%)

5 (10)

2 (18)

3 (8)

0.29

Beta-blocker use, n (%)

26 (51)

5 (46)

21 (53)

0.68

ACEI/ARB use, n (%)

27 (53)

6 (55)

21 (53)

0.90

11 (22)

3 (27)

8 (20)

0.603

Furosemide, n (%)

5 (13)

0.211

Amiodarone, n (%)

15 (29)

6 (55)

9 (23)

0.039

Body surface area, m2

mineralocorticoid receptor antagonists, n

(%)

Implanted cardiac device, n (%)

p-value

0.534

Pacemaker, n (%)

11 (22)

3 (27)

8 (20)

ICD, n (%)

5 (10)

2 (18)

3 (8)

CRTD, n (%)

3 (6)

3 (8)

0.84±0.28

0.80±0.21

0.85±0.30

0.59

109 (92–212)

174 (56–327)

0.36

Creatinine, mg/dL

BNP level, pg/mL

154 (62–

293)

ACE elevation (> 29.4 IU/L), n (%)

6 (12)

6 (15)

0.17

sIL-2R elevation (> 613 U/ml), n (%)

14 (28)

2 (18)

12 (30)

0.44

Extracardiac sarcoidosis, n (%)

32 (63)

5 (46)

27 (68)

0.18

Eye, n (%)

8 (16)

2 (18)

6 (15)

0.80

Lung, n (%)

26 (51)

3 (27)

23 (58)

0.08

Skin, n (%)

3 (6)

1 (9)

2 (5)

0.61

Arrhythmic event, n (%)

30 (59)

9 (89)

21 (53)

0.08

FDG-PET abnormality, n (%)

50 (98)

10 (91)

40 (100)

0.054

LGE on CMR, n (%)

33 (97)

5 (46)

26 (65)

0.24

ACE, angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; ARB,

angiotensin II receptor blocker; BNP, brain natriuretic peptide; FDG-PET, fluorodeoxyglucose

positron emission tomography; LGE, late gadolinium enhancement; NYHA, New York Heart

Association; RV, right ventricle; RVD, right ventricular dysfunction; sIL-2R, soluble

interleukin-2 receptor; CMR, cardiac magnetic resonance imaging.

Table 2. Criteria for Cardiac Involvement According to JCS Guidelines

All

N = 51

Event

No event

n=11

n=40

(22%)

(78%)

pvalue

1. Major criteria

(a) High-grade atrioventricular block or fatal

ventricular arrhythmia

High-grade atrioventricular block, n (%)

20 (39)

6 (55)

14 (35)

0.24

Ventricular tachycardia, n (%)

15 (30)

7 (64)

8 (20)

0.005

Ventricular fibrillation, n (%)

2 (4)

2 (5)

0.449

Basal thinning of the ventricular septum, n (%)

21 (41)

7 (64)

14 (35)

0.09

Abnormal ventricular wall anatomy, n (%)

12 (24)

2 (18)

10 (26)

0.609

Left ventricular ejection fraction < 50%, n (%)

25 (49)

5 (46)

20 (50)

0.789

Regional wall motion abnormality, n (%)

39 (77)

9 (82)

30 (75)

0.64

50 (98)

10 (91)

40 (100)

0.054

34 (97)

5 (46)

26 (65)

0.24

30 (67)

6 (55)

24 (71)

0.327

0 (0)

25 (49)

6 (55)

19 (48)

0.68

(b) Basal thinning of the ventricular septum or

abnormal ventricular wall anatomy (aneurysm,

thinning, thickening of ventricular wall)

regional wall motion abnormality

(d) Abnormal cardiac accumulation on 67Ga citrate

scintigraphy of FDG-PET, n (%)

(e) Late gadolinium enhancement on CMR, n (%)

2. Minor criteria

(f) Abnormal ECG findings: ventricular arrhythmias

(nonsustained VT, multifocal or frequent PVC),

bundle branch block, axis deviation, or abnormal

Q waves, n (%)

(g) Perfusion defects on myocardial perfusion

scintigraphy (SPECT), n (%)

(h) Endomyocardial biopsy: monocyte infiltration and

moderate or severe myocardial interstitial fibrosis,

n (%)

Abbreviations: CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; JCS,

Japanese circulation society; FDG-PET, 18F-fluorodeoxyglucose positron emission

tomography; PVC, premature ventricular contraction; SPECT, single-photon emission

computed tomography; VT, ventricular tachycardia.

Table 3. Echocardiographic characteristics at baseline according to events.

Entire cohort

n=51

Event

No event

n=11

n=40

(22%)

(78%)

p-value

LVEDVi, mL/m2

78±34

72±24

80±36

0.47

LVESVi, mL/m2

34.5 (24–53)

32 (27–46)

35 (24–54)

0.87

LVEF, %

50±14

47±12

50±14

0.49

Basal IVS thinning, n (%)

21 (41)

7 (64)

14 (35)

0.09

Aneurysm, n (%)

12 (24)

2 (18)

10 (25)

0.64

39 (77)

9 (82)

30 (75)

0.64

LVEF <50% n (%)

25 (49)

5 (46)

20 (50)

0.79

LVMi, g/m2

115±33

122±36

114±32

0.48

Regional wall motion

abnormality, n (%)

E/A

0.84 (0.71–1.16) 0.92 (0.71–1.57) 0.83 (0.71–1.13)

0.62

E/e’

10.4 (7.5–13.6)

9.8 (6.8–13.3)

10.6 (7.5–14.3)

0.66

38±15

36±13

39±16

0.67

-12.3±4.5

-12.0±3.6

-12.3±4.8

0.85

MR ≥ moderate, n (%)

18 (35)

1 (9)

17 (43)

0.04

TR ≥ moderate, n (%)

6 (12)

2 (18)

4 (10)

0.46

2.24 (1.94-2.43)

2.24 (2.04-2.38)

2.25 (1.93-2.44)

0.98

21±4

20.5±5.4

20.8±3.5

0.84

S’, cm/s

11.5±2.3

10.9±2.5

11.6±2.3

0.47

FAC, %

36±10

34±11

37±9

0.45

-19.1±5.2

-15.7±4.0

-20.1±5.1

0.013

LAVi, mL/m2

LV GLS, %

TR velocity, m/sec

TAPSE, mm

RVFWLS, %

IVS, interventricular septum; FAC, fractional area change; GLS, global longitudinal strain;

LAVi, left atrial volume index; LV, left ventricular; LVEDVi, left ventricular end-diastolic

volume index; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end-systolic

volume index; LVMi, left ventricular mass index; MR, mitral regurgitation; RVD, right

ventricular dysfunction; RVFWLS, right ventricular free wall longitudinal strain; S’, tricuspid

lateral annular systolic velocity on tissue Doppler imaging; TAPSE, tricuspid annular plane

systolic excursion; TR, tricuspid regurgitation.

Table 4. Treatment after diagnosis

Entire cohort

n=51

Event

No event

n=11

n=40

(22%)

(78%)

Steroid maintenance dose, mg

0.074

Steroid dose £ 5 mg, n (%)

23 (48)

6 (60)

17 (45)

Steroid dose > 5 - 10 mg, n (%)

24 (50)

3 (30)

21 (55)

1 (2)

1(9)

Steroid dose >10 mg, n (%)

p-value

Implanted cardiac device, n (%)

0.555

Pacemaker, n (%)

6 (12)

1 (9)

5 (13)

ICD, n (%)

5 (10)

1 (9)

4 (10)

CRTD, n (%)

7 (14)

3 (27)

4 (10)

Methotrexate, n (%)

7 (14)

3 (27)

4 (10)

0.140

Azathioprine, n (%)

1 (2)

1 (3)

0.592

ICD, Implantable cardioverter defibrillator; CRTD cardiac resynchronization therapy (CRTD).

Table 5. Cox proportional hazards model for composite endpoints of cardiovascular

events.

Univariable

Multivariable

HR (95% CI)

p-value

Age, years

1.04 (0.97–1.11)

0.26

Female sex

1.18 (0.34–4.04)

0.80

Atrioventricular block at baseline

1.53 (0.46-5.11)

0.49

Sustained VT at baseline

5.26 (1.54-18.05)

0.008

LVEF, %

0.97 (0.93–1.02)

0.25

LV GLS, %

1.03 (0.89-1.18)

0.72

TR velocity, m/sec

1.78 (0.54–5.80)

0.34

TAPSE, mm

0.96 (0.82–1.14)

0.67

S’, cm/s

0.89 (0.65–1.22)

0.47

FAC, %

0.97 (0.92–1.03)

0.37

RVFWLS, %

1.29 (1.07–1.57)

0.008

HR (95% CI)

p-value

4.20 (1.16-15.17)

0.028

1.22 (1.03–1.46)

0.025

CI, confidence interval; FAC, fractional area change; GLS, global longitudinal strain; HR,

hazard ratio; LV, left ventricular; LVEF, left ventricular ejection fraction; RVFWLS, right

ventricular free wall longitudinal strain; S’, tricuspid lateral annular systolic velocity on tissue

Doppler imaging; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid

regurgitation; VT, ventricular tachycardia.

Table 6. Paired comparison for RV conventional and RVFWLS parameters according

to the RV systolic function at the baseline and 1-year follow-up.

Event

p-value†

No event

Baseline

Follow-up

p-value* Baseline

Follow-up

p-value*

TAPSE, mm

20.5±5.4

17.7±3.6

0.06

20.8±3.5

20.5±4.0

0.43

0.07

S’, cm/s

11.0±2.5

10.3±1.8

0.65

11.6±2.3

11.0±1.6

0.16

0.28

FAC, %

33.9±11.3

33.3±10.6

0.79

36.6±9.4

37.6±9.6

0.44

0.39

RVFWLS, %

-15.7±4.0

-14.5±2.6

0.09

-20.1±5.1

-20.8±5.4

0.56

0.002

LVEF, %

47.2±12.1

50.3±10.8

0.11

50.2±14.2

53.3±13.9

0.40

0.56

LV GLS, %

-12.0±3.6

-10.5±2.8

0.13

-12.3±4.8

-14.5±4.3

0.004

0.014

*Comparison between baseline and follow-up in the same group performed using paired test.

†Comparison between follow-up in the event and event-free groups performed using unpaired

test.

FAC, fractional area change; GLS, global longitudinal strain; LV, left ventricular; LVEF, left

ventricular ejection fraction; RV, right ventricular; RVFWLS, right ventricular free wall

longitudinal strain; S’, tricuspid lateral annular systolic velocity on tissue Doppler imaging;

TAPSE, tricuspid annular plane systolic excursion.

Table 7. Patients’ characteristics according to the RVFWLS

Reduced RVFWLS:

Preserved RVFWLS:

>-16.8%

≤-16.8%

N = 18 (35%)

N = 33 (65%)

BNP, pg/mL

223 (109-437)

113 (51-201)

0.032

LVEDVi, mL/m2

84±42

75±29

0.40

LVESVi, mL/m2

38 (27-80)

31 (21-47)

0.10

LVEF, %

42.4±11.9

53.4±13.3

0.005

LV GLS, %

-10.4±3.9

-13.3±4.6

0.049

TR velocity, m/sec

2.31 (2.03-2.84)

2.22 (1.90-2.42)

0.18

p-value

BNP, brain natriuretic peptide; GLS, global longitudinal strain; LAVi, left atrial volume index;

LV, left ventricular; LVEDVi, left ventricular end-diastolic volume index; LVEF, left

ventricular ejection fraction; LVESVi, RVFWLS, right ventricular free wall longitudinal

strain; TR, tricuspid regurgitation.

Table 8. Association between RV uptake on 18F-fluorodeoxyglucose positron emission

tomography and echocardiographic parameters.

FDG-PET

RV uptake (+)

RV uptake (-)

n=19 (38%)

n=26 (62%)

51±11

48±15

0.59

LV GLS, %

-12.2±3.6

-12.3±5.0

0.91

TAPSE, mm

20±5

21±3

0.49

S’, cm/s

11.2±2.8

11.7±2.1

0.53

FAC, %

30.0±10.0

39.3±8.1

0.001

5 (56)

14 (34)

0.27

-17.0±3.9

-20.6±5.5

0.018

P-value

LVEF, %

RVD by conventional parameters, n (%)

RVFWLS, %

FAC, fractional area change; GLS, global longitudinal strain; LV, left ventricular LVEF, left

ventricular ejection fraction; RV, right ventricular; RVD, right ventricular dysfunction;

RVFWLS, right ventricular free wall longitudinal strain; S’, tricuspid lateral annular systolic

velocity on tissue Doppler imaging; TAPSE, tricuspid annular plane systolic excursion.

Table 9. Association between RV Late gadolinium enhancement on cardiac magnetic

resonance imaging and echocardiographic parameters.

CMR

RV LGE (+)

RV LGE (-)

P-value

n=15 (44%)

n=19 (65%)

LVEF, %

49±10

52±16

0.49

LV GLS, %

12±3

13±5

0.35

TAPSE, mm

20±5

21±3

0.64

S’, cm/s

12±3

12±2

0.89

FAC, %

32±10

39±8

0.046

RVD by conventional parameters, n (%)

4 (27%)

1 (5%)

0.08

RVFWLS, %

16.6±4

20.5±5

0.022

FAC, fractional area change; GLS, global longitudinal strain; LV, left ventricular; LVEF, left

ventricular ejection fraction; RV, right ventricular; RVD, right ventricular dysfunction;

RVFWLS, right ventricular free wall longitudinal strain; S’, tricuspid lateral annular systolic

velocity on tissue Doppler imaging; TAPSE, tricuspid annular plane systolic excursion.

Table 10. LGE distribution and FDG accumulation according to the baseline RVFWLS

(N = 33).

Reduced RVFWLS:

Preserved RVFWLS:

>-16.8%

≤-16.8%

N= 13 (39%)

N=20 (61%)

31 ± 16

26 ± 24.6

0.558

Basal septum, n (%)

12 (92)

16 (80)

0.335

Mid septum, n (%)

11 (85)

11 (55)

0.078

LV anterior wall, n (%)

9 (69)

8 (40)

0.101

LV anterolateral wall, n (%)

7 (54)

12 (60)

0.727

LV inferolateral wall, n (%)

5 (39)

8 (62)

0.93

LV Inferior wall, n (%)

8 (62)

12 (60)

0.930

LV apex, n (%)

3 (23)

5 (25)

0.900

RV free wall, n (%)

10 (83)

5 (25)

0.001

RV septum, (%)

11 (85)

10 (50)

0.043

Basal septum, n (%)

9 (69)

15 (75)

0.716

Mid septum, n (%)

11 (85)

13 (65)

0.216

LV anterior wall, n (%)

7 (54)

6 (30)

0.171

LV anterolateral wall, n (%)

8 (62)

16 (80)

0.245

LV inferolateral wall, n (%)

8 (62)

14 (70)

0.614

LV Inferior wall, n (%)

7 (54)

9 (45)

0.619

LV apex, n (%)

7 (54)

10 (50)

0.829

RV free wall, n (%)

8 (62)

7 (35)

0.135

P value

CMR data

LGE mass in LV, g

Segmental LGE distribution

FDG-PET data

Regional uptake

CMR, cardiac magnetic resonance imaging; 18F-fluorodeoxyglucose positron emission

tomography; LGE, late gadolinium enhancement; left ventricular, LV; RV, right ventricular;

RVFWLS, right ventricular free wall longitudinal strain

Table 11. Catheter ablation details

Patients

no.

Age

(years)

Gender

LVEF

(%)

RVFWLS

(%)

male

-20.0

LV septum

RV septum

LV septum

RV septum

male

-17.0

RV septum

female

-15.7

Normal voltage

LV anterolateral

wall

Low voltage area

Ablation site

female

-16.0

LV septum

RV septum

LV septum

RV septum

LVOT

RVOT

male

-21.7

Normal voltage

RV septum

male

-11.8

RV free wall

LV anterior wall

female

-12.0

RV septum

LVOT

RVOT

LV left ventricular; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow

tract, RV, right ventricular; RVFWLS, right ventricular free wall longitudinal strain, RVOT;

right ventricular outflow tract.

15- Figures

Figure1. Histopathological findings of cardiac sarcoidosis.

Representative image of endomyocardial biopsy specimen in a study population (hematoxylin

and eosin stain). The myocardial specimen obtained from right ventricular septum showed noncaseating epithelioid cell granulomas (arrow).

Figure 2. Echocardiographic parameters for right ventricular function assessment

Fractional

area

change

(FAC)

(S’)

(TAPSE)

Tissue

doppler

M-Mode

20cm/s

ESA 14.4cm2

FAC 47%

EDA 26.9cm2

FAC%

TAPSE

S’ wave

Diastolic

phase

Systolic

shortening

This figure shows echocardiographic parameters for the right ventricular function assessment

parameters: Fractional area change (FAC), Tricuspid annular plane systolic excretion (TAPSE),

Tricuspid lateral annular systolic velocity (S’).

Right

ventricular

free

wall

strain

(RVFWLS%)

Figure 3. Right ventricular free wall longitudinal strain (RVFWLS)

(A) Schematic figure for the strain analysis

The strain can be evaluated as the change of the length in one direction from the reference time

(L0) to a given point in time (L(t)) and described as a percent. The reference time is usually

taken at end-diastole and the length in systole is less than the length in diastole so the value of

strain would be negative number if their myocardial function is normal.

(B) Preserved RVFWLS

RVFWLS%= -30%

RVFWLS%= -7.8%

The larger absolute number of the strain means better longitudinal ventricular function, while

lower absolute number of the strain means deteriorated ventricular function. Patients with

RVFWLS = -30% (B), the absolute number is 30 which indicated good RV function, while a

patient with RVFWLS = - 7.8 % (C), the absolute number is 7.8, indicating RV dysfunction.

Figure 4. Study flow diagram

CS by JCS criteria (2012-2020)

N = 60

Inclusion creteria

• Patients with cardiac sarcoidosis.

• Patients who have a one-year follow-up.

• Good echocardiographic image quality.

Patients who were followed in

another institute N=6

Inadequate image quality N=2

No baseline echo data N=1

Study population

N = 51

Figure 5. Speckle tracking imaging, 18F-fluorodeoxyglucose positron emission

tomography, and cardiac magnetic resonance imaging evaluation of right ventricle.

RVFWLS -15.7%

The figure shows right ventricular free wall longitudinal strain (RVFWLS; A),

F-

fluorodeoxyglucose on fluorodeoxyglucose positron emission tomography evaluation (FDGPET; B), and cardiac magnetic resonance imaging (CMR; C) in cardiac sarcoidosis patient.

RVFWLS was estimated by assessing the average longitudinal strain in the RV free wall

segment after excluding the septal component. RVFWLS was estimated to be -15.7 %,

indicating deterioration of RV longitudinal systolic function. FDG-PET showed intense uptake

in the RV free wall (arrow). CMR also showed late gadolinium enhancement in the RV free

wall (arrow).

Figure 6. Segmental evaluation of RV and LV involvement.

Simplified Segmentation

17-segment Model (AHA)

Basal anterior

Basal anteroseptal

Basal inferoseptal

Basal inferior

Basal inferoalateral

Basal anterolateral

7. Mid anterior

8. Mid anteroseptal

9. Mid inferoseptal

10. Mid inferior

11. Mid inferolateral

12. Mid anterolateral

13. Apical anterior

14. Apical septal

15. Apical inferior

16. Apical lateral

17. Apex

18. RV septum

19. RV free-wall

Basal septal

Mid septal

Inferior

Inferolateral

Anterolateral

7. Apex

8. RV septum

9. RV free-wall

LV myocardial segmentation was performed using the American Heart Association 17segment model [27]. For analysis, we simplified the LV segmentation; for septal segments,

anteroseptal and inferoseptal segments in basal and mid were considered the same segment. As

for remaining anterior, anterolateral, inferolateral, and inferior segments, basal and mid

segments were merged and considered as the same segment. Four apical segments and an apex

were exhibited as one segment. The endocardial RV surface was divided into RV-free wall and

septum.

Figure 7. Flow diagram of diagnosis of cardiac sarcoidosis according to JCS guidelines

Abbreviations: CS, cardiac sarcoidosis; JCS, Japanese circulation society

Clinical or Histological diagnosis of extracardiac sarcoidosis

N=32

Yes

N=4

EMB positive

Yes

N=19

N=28

Major criteria ≥ 4/5

Including positive FDG-PET

Major criteria ≥ 2 or

1 major AND ≥ 2 minor criteria

Histological

diagnosis

Clinical

diagnosis

Isolated CS

CS with extracardiac involvement

Major Criteria

• Heart block, fatal ventricular arrhythmia

• Basal IVS thinning, abnormal wall anatomy

• LVEF < 50% or wall motion abnormality

• Cardiac uptake in FDG-PET or Ga scintigraphy

• LGE on CMR

Minor Criteria

• Abnormal ECG findings: ventricular arrythmia, bundle

branch block, axis deviation, abnormal Q wave

• Perfusion defect on SPECT

• Interstitial fibrosis or monocyte infiltration on EMB

Figure 8. Impact of baseline RVFWLS on outcomes in patients with cardiac sarcoidosis.

MACE free survival

1.0

0.8

0.6

T1: < -21.0%

T2: -21.0 to 16.8%

T3: > -16.8%

0.4

P = 0.002

0.2

T1 vs. T2: P = 0.65

T1 vs. T3: P = 0.002

T2 vs. T3: P = 0.021

0.0

Follow-up, years

Pts. at risk

Kaplan-Meier curves demonstrated MACE-free survival in patients with cardiac sarcoidosis

according to the RVFWLS tertiles. Patients with RVFWLS >-16.8% (third tertile) had lower

MACE-free survival than those in the other groups (p=0.002).

MACE, major adverse cardiovascular event; RVFWLS, right ventricular free wall longitudinal

strain; T, tertile.

Figure 9. Receiver-operating characteristic curves to detect patients with major adverse

cardiovascular events.

1.0

Sensitivity

0.8

0.6

0.4

RVFWLS (AUC 0.74)

S’ (AUC 0.60)

TAPSE (AUC 0.54)

FAC (AUC 0.48)

Reference Line

0.2

0.0

0.2

0.4

0.6

0.8

1.0

1 - Specificity

Baseline right ventricular free wall longitudinal strain (RVFWLS) showed the highest area

under the curve (AUC: 0.74) among echocardiographic markers of right ventricular function

at the baseline to detect major adverse cardiovascular events.

FAC, fractional area change; TAPSE, tricuspid annular plane systolic excretion.

Figure 10. Changes in echocardiographic parameters during steroid therapy in cardiac

sarcoidosis patients with and without events.

-5.0

RVFWLS (%)

Event

-10.0

TAPSE (mm)

24.0

16.0

No event

22.0

14.0

20.0

-15.0

TV-S’ (cm/s)

No event

12.0

18.0

10.0

16.0

-20.0

-25.0

-30.0

45.0

p = 0.11*

No event

10.0

Follow-up

8.0

Event

p = 0.94*

6.0

*Difference in TAPSE change between groups

Baseline

FAC (%)

Follow-up

70.0

Event

-10.0

4.0

LV GLS (%)

-5.0

No event

40.0

Event

12.0

*Difference in RVFWLS change between groups

Baseline

p = 0.14*

14.0

60.0

*Difference in S’ chang ...

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