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Oyama-Manabe, Manabe, Aikawa, and Tsuneta: The Role of Multimodality Imaging in Cardiac Sarcoidosis
State of the Art Review

Korean Circulation Journal 2021; 51(7): 561-578.

Published online: 10 May 2021

DOI: https://doi.org/10.4070/kcj.2021.0104

The Role of Multimodality Imaging in Cardiac Sarcoidosis

Noriko Oyama-Manabe, MD, PhD1, *, Osamu Manabe, MD, PhD1, *, Tadao Aikawa, MD, PhD1, 2, Satonori Tsuneta, MD3

1Department of Radiology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

2Department of Cardiology, Hokkaido Cardiovascular Hospital, Sapporo, Japan.

3Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital, Sapporo, Japan.

Correspondence to Noriko Oyama-Manabe, MD, PhD. Department of Radiology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-Cho, Omiya-ku, Saitama 330-8503, Japan. norikomanabe@jichi.ac.jp

Equal contributor:

*Dr. Noriko Oyama-Manabe and Osamu Manabe equally contributed this article.

Received 30 March 2021       Accepted 21 April 2021

Copyright © 2021. The Korean Society of Cardiology

The Korean Society of Cardiology

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Author's summary

Cardiac sarcoidosis (CS) is significantly associated with a poor prognosis due to the associated congestive heart failure, arrhythmias (such as an advanced atrioventricular block), and ventricular tachyarrhythmia. Novel imaging modalities are now available to detect CS lesions secondary to active inflammation, granuloma formation, and fibrotic changes such as 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and cardiac magnetic resonance imaging (CMR). Systematic review revealed both modalities showed high sensitivity to detect CS, while FDG PET and CMR provide different aspects of the pathophysiology of CS.

Abstract

The etiology and the progression of sarcoidosis remain unknown. However, cardiac sarcoidosis (CS) is significantly associated with a poor prognosis due to the associated congestive heart failure, arrhythmias (such as an advanced atrioventricular block), and ventricular tachyarrhythmia. Novel imaging modalities are now available to detect CS lesions secondary to active inflammation, granuloma formation, and fibrotic changes. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and cardiac magnetic resonance imaging (CMR) play essential roles in diagnosing and monitoring patients with confirmed or suspected CS. The following focused review will highlight the emerging role of non-invasive cardiac imaging techniques, including FDG PET/CT and CMR.

Keywords: Cardiac sarcoidosis, 18F-FDG PET, Cardiac magnetic resonance imaging

INTRODUCTION

Sarcoidosis is a chronic multi-system inflammatory disorder of unknown etiology characterized pathologically by the formation of non-caseating granulomas in the involved organs or tissues. Essentially, any body tissue may be affected,1)2) but the most commonly involved include the lymph nodes, skin, lung, musculoskeletal system, and eyes.
Although the overall prognosis of patients with systemic sarcoidosis is generally favorable, cardiac sarcoidosis (CS) is significantly associated with a poor prognosis due to congestive heart failure, arrhythmias (such as an advanced atrioventricular block), and ventricular tachyarrhythmia.3)4) Thus, an early and precise diagnosis of CS is essential. Recent studies have demonstrated the usefulness of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and cardiac magnetic resonance imaging (CMR) for assessing CS. In this review, we focus on the pathophysiology and diagnostic aspects of CS with multimodality imaging.

ETIOLOGY

The incidence of sarcoidosis and its cardiac involvement varies among ethnic groups and regions.5)6) Symptomatic CS has been reported in up to 10% of the patients with systemic sarcoidosis.7)8)9)10) An autopsy series from the United States and Japan showed that approximately 27% and 80% of patients with systemic sarcoidosis, respectively, had CS.11)12) Recent advances in cardiac imaging tools have enabled the detection of asymptomatic CS.13) As such, imaging series have reported higher rates of cardiac involvement in patients with extra-CS, ranging from 19% to 55% for asymptomatic CS.4)8)13)14)15)

PATHOLOGICAL CHARACTERISTICS OF CARDIAC SARCOIDOSIS

The pathological hallmark of CS is the non-caseating epithelioid granuloma with a compact central area of macrophages and scattered lymphocytes.1) If there is active inflammation, the granuloma can progress to irreversible fibrosis.16) The myocardium of the left ventricular free wall is the most common location of sarcoid involvement, followed by the interventricular septum, papillary muscles, right ventricle, and atria.17)18) An endomyocardial biopsy is a valuable tool in the definitive diagnosis of CS,19) but it is limited owing to its low sensitivity due to the patchy distribution of granulomas and its complications.

CLINICAL PRESENTATION

CS manifestations can range widely from a clinically asymptomatic form to sudden cardiac death.20) Arrhythmic, cardiomyopathic, and pericardial manifestations are common clinical signs and symptoms (Table 1).20)21)22)23)24)25)
Table 1

Clinical presentations of cardiac sarcoidosis

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Clinical manifestation Prevalence (%)
Arrythmias
Atrioventricular block 23–77.4
Bundle branch block 12–66
Atrial tachycardia 0–15
Ventricular tachycardia 2–42
Sudden cardiac death 12–65
Cardiomyopathy
Heart failure 10–30
Pericardial disease
Pericardial effusion 2–20
Pericarditis Rare
Atrioventricular conduction disease due to the infiltration of sarcoid granulomas is the most common finding in patients with CS.26) Ventricular and atrial arrhythmias are also frequent manifestations, with the latter being caused by atrial dilation secondary to left ventricular dysfunction and the atrial infiltration of sarcoid granulomas. Both systolic and diastolic ventricular dysfunction can result from granulomatous inflammation and subsequent scarring, subsequently leading to heart failure. Meanwhile, pulmonary infiltration may lead to right ventricular failure. Less commonly, CS may manifest as progressive pericardial diseases, such as pericarditis or tamponade.

CRITERIA FOR THE DIAGNOSIS OF CARDIAC SARCOIDOSIS

CS is conventionally diagnosed by the appropriate combination of clinical and physiological signs and symptoms and multimodal imaging. Several diagnostic criteria have been proposed, and one commonly used is the Japanese Ministry of Health and Welfare criteria,27)28) modified in 2015 by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders (Table 2).25) The Heart Rhythm Society Expert Consensus Statement of the CS was also published in 2014 (Table 3).29) In these 2 criteria, the diagnosis is separated by histological and clinical methods. To confirm the histological diagnosis, the presence of non-caseating epithelioid granulomas from the endomyocardial biopsy sample should be demonstrated. The histological analysis of operative or endomyocardial biopsy specimens could be the gold standard. However, endomyocardial biopsy cannot be performed on all suspected regions and has a lower sensitivity in diagnosing CS.19) On the contrary, the clinical diagnosis correlates the histological diagnosis of extra-cardiac sarcoidosis with the electrocardiographic and imaging findings, including echocardiography, 67Ga scintigraphy, 18F-FDG PET, and late gadolinium enhancement on CMR.
Table 2

Japanese Society of Sarcoidosis and Other Granulomatous Disorders 2015 criteria for cardiac sarcoidosis25)

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1. Histological diagnosis group
Cardiac sarcoidosis is confirmed when endomyocardial biopsy specimens demonstrate non-caseating epithelioid cell granulomas with a histological or clinical diagnosis of extra-cardiac sarcoidosis.
2. Clinical diagnosis group
Cardiac sarcoidosis is confirmed when, although endomyocardial biopsy specimens do not demonstrate non-caseating epithelioid cell granulomas, extra-cardiac sarcoidosis is diagnosed histologically or clinically and the following conditions and the following diagnostic criteria are satisfied:
a) Two or more of the 5 major criteria are met
OR
b) One of the 5 major criteria and 2 or more of the 3 minor criteria are met
Major criteria
1) Advanced atrioventricular block or sustained ventricular tachycardia
2) Basal thinning of the interventricular septum or morphological abnormality (aneurysm, wall thinning, or wall thickening)
3) Depressed ejection fraction (<50%) or regional wall motion abnormality
4) Abnormal uptake of 67Ga or 18F-fluorodeoxyglucose in the heart
5) Delayed gadolinium enhancement on cardiac magnetic resonance
Minor criteria
1) Abnormal electrocardiographic findings: ventricular arrhythmias (non-sustained ventricular tachycardia or multifocal or frequent premature ventricular contractions), bundle branch block, axis deviation, or abnormal Q-waves
2) Perfusion defects on nuclear imaging
3) Endomyocardial biopsy: interstitial fibrosis or monocyte infiltration of moderate grade
Table 3

Heart Rhythm Society's Expert Consensus Statement for diagnosis of CS29)

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1. Histologic diagnosis
Non-caseating granuloma on endomyocardial biopsy without alternative cause
2. Clinical diagnosis
a) Histologic diagnosis of extra-CS
And
b) One of the following is present
1) Steroid responsive cardiomyopathy or heart block
2) Unexplained LVEF <40%
3) Unexplained sustained VT
4) Advanced heart block
5) Patchy uptake on cardiac PET
6) LGE on CMR
7) Positive 67Ga uptake
And
c) Other causes for the cardiac manifestation(s) have been excluded
CMR = cardiac magnetic resonance imaging; CS = cardiac sarcoidosis; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; PET = positron emission tomography; VT = ventricular tachycardia.

18F-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY

PET is a highly sensitive and non-invasive molecular imaging technique that can visualize and quantify the active processes of physiological function and disease conditions, in contrast to anatomical approaches. 18F-FDG is a glucose analog widely used to visualize and quantify glucose metabolism in the target region since it is taken up by plasma membrane glucose transporters (GLUT) in living cells and phosphorylated by intracellular hexokinase into 18F-FDG-6-phosphate (18F-FDG-6-P) similar to glucose. 18F-FDG-6-P is retained within the cell without further metabolism along the glycolytic pathway, a phenomenon known as metabolic trapping. Therefore, tissue activity can be directly visualized using 18F-FDG PET.

Cardiac metabolism and preparation to suppress the physiological 18F-fluorodeoxyglucose uptake

Under normal conditions, free fatty acids (FFAs) and glucose are the major energy sources for cardiac metabolism. Since the 18F-FDG is an analog of glucose, its physiological accumulation in the myocardium has a causal influence on the false-positive diagnosis of CS.30) The fasting state has a significant effect on the physiological uptake. Figure 1 shows a representative case of various physiological uptakes during follow-up in one patient (non-CS case). Under long fasting conditions, glucose production and glucose oxidation decrease, leading to the release of available FFA from adipose tissue to provide an alternative energy source. The physiological uptake of 18F-FDG in the myocardium can be suppressed with a low-carbohydrate diet and a high-fat diet due to the switch to FFA metabolism. As such, FFA level is an important marker of physiological 18F-FDG uptake suppression.31)
Figure 1

A representative case of various physiological myocardial uptake patterns during follow-up in one patient.

A patient with malignant lymphoma underwent serial 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans for follow-up after chemotherapy. Focus on the left ventricular uptake, no uptake (A), diffuse strong uptake with left ventricular uptake (B), predominant regional uptake in the base of the myocardium (C), and diffuse uptake (D) is pointed out.
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18F-fluorodeoxyglucose accumulation in sarcoidosis lesion

The significant 18F-FDG accumulation in sarcoidosis lesions is caused by activated inflammatory cells, such as neutrophils, macrophages, and lymphocytes; GLUT1 and GLUT3 in the cell membrane; and hexokinase.32)33) As 18F-FDG uptake reflects active inflammation, it is therefore useful in detecting CS and guiding immunosuppression management.34) Figure 2 shows a representative case of CS before and after steroid therapy.
Figure 2

A representative case of a woman in her 60s with complete right bundle branch block before and after steroid therapy. Cardiac magnetic resonance shows subepicardial gadolinium enhancement at the basal septum and lateral wall (A). Focal myocardial fluorodeoxyglucose uptake at the septum and multiple uptake at the mediastinal lymph nodes are consistent with cardiac sarcoidosis (B). After administration of steroid therapy, myocardial and mediastinal uptake are diminished (C).

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Myocardial 18F-FDG uptake patterns are conventionally divided into 4 groups: none, diffuse, focal, and focal on diffuse.35)36) When myocardial 18F-FDG uptake is absent, it is negative for active CS lesions. Definite diffuse 18F-FDG uptake in the entire left ventricular wall is generally a physiological uptake and does not indicate an abnormality. On the contrary, focal and focal on diffuse 18F-FDG uptake in the left ventricular wall are considered positive for CS. In addition, the diffuse at base uptake pattern is known to be associated with inadequate physiologic suppression.37)
The combination of 18F-FDG and perfusion findings has led to improvements in the accurate diagnoses and prognostication.3)
With its high diagnostic value and high inter-rater reproducibility, 18F-FDG PET texture analysis can also be used to diagnose CS, focusing on its heterogeneous distribution.38) Texture analysis can differentiate abnormal and physiological CS uptake.

CARDIAC MAGNETIC RESONANCE IMAGING

Late gadolinium enhancement

CMR offers both functional and structural information to help detect the acute and chronic inflammatory phases of CS. In contrast, it does not require specific preparation such as long fasting before examination as required for 18F-FDG PET; however, it is contraindicated in patients with MR unsafe or some MR conditional implantable devices.
CMR with late gadolinium enhancement (LGE) is an emerging tool for evaluating CS. Mid-wall or subepicardial LGE in the basal ventricular wall, lateral wall, and septum (Figure 2) is the most common pattern seen in CS,4) recently confirmed in a meta-analysis of studies with histological confirmation.39)
Myocardial enhancement on LGE-CMR images adds an independent prognostic value for the risk stratification sarcoidosis patients.40)41) Greulich et al.8) also reported that the presence of LGE was the best independent predictor of death and other adverse events in CS. However, it is difficult to differentiate active inflammation from chronic fibrosis using LGE alone.

T1/T2 mapping

CMR mapping techniques such as T1, T2, and extracellular volume can provide additional quantitative information regarding interstitial changes. In combination with LGE, CMR mapping can significantly improve the diagnosis of subclinical CS.42) Greulich et al.43) compared 61 patients with sarcoidosis and 26 healthy patients and found that the former had significantly higher native T1, T2, and extracellular volume. The weighted mean T1 value at 1.5 T of 994 ms (range, 975–1,039 ms) in the patients with sarcoidosis was significantly higher than the controls (960 ms; range, 942–986 ms), independent of the presence of LGE. Meanwhile, the patients with sarcoidosis had a weighted mean T2 value at 1.5 T of 52.3 ± 3.8 ms, higher than the 49.0 ± 1.6 ms in the controls. At 3 T, the values were 54.0 ± 12.2 ms and 45.0 ± 10.8 ms, respectively.44) Figure 3 shows active CS with LGE-CMR and T2 mapping, which correlate with positive 18F-FDG PET findings. T2 mapping provides an absolute and objective parameter for active inflammation. Native T1 and T2 mapping could be used for disease monitoring and differentiating sarcoid patients from healthy controls without the use of gadolinium.45)
Figure 3

A woman in her 60s was admitted to the hospital with acute heart failure. Cardiac magnetic resonance imaging shows abnormal gadolinium enhancement with transmural and epicardium distribution of left ventricle (A, arrows). Through T2 mapping, the diffuse prolongation of T2 values is observed, suggesting myocardial edema or inflammation due to active cardiac sarcoidosis (B, normal range was under 54 ms). 18F-fluorodeoxyglucose positron emission tomography/computed tomography reveals correlated focal uptake, confirming active cardiac sarcoidosis (C, arrows).

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Strain imaging

Myocardial strain analysis has been developed to objectively evaluate the regional myocardial function, including longitudinal, circumferential, radial, and rotational myocardial strains.46) Among these, left ventricular global longitudinal strain (GLS) has been receiving the most attention because subendocardial fibers originate longitudinally and thus, may be sensitive in detecting early changes in various cardiomyopathies. Two-dimensional speckle tracking echocardiography has been used to evaluate CS. GLS and global circumferential strain were significantly lower in extra-cardiac sarcoidosis patients despite not exhibiting any cardiac symptoms.47) Impaired GLS is associated with major cardiac events in patients with CS.47) Due to its association with cardiac events in patients with sarcoidosis, a recent study also reported that biventricular strain deterioration can be used as an early marker of cardiac involvement.48)
Similar to speckle tracking echocardiography, CMR techniques for assessing myocardial strain, such as tagging,49) strain-encoded (SENC) magnetic resonance imaging (MRI),50)51) and myocardial feature-tracking deformation imaging (FTI),52) have the potential to detect a wide range of myocardial diseases early, accurately, and without the need for contrast agent injection. A small study using SENC for CS has been reported.53) Specifically, FTI is also useful for evaluating regional and global strains, well correlated with SENC MRI.54) This method requires only cine images without specific extra scanning. Dabir et al.55) reported that GLS assessed with FTI was reduced in patients with a negative outcome, possibly serving as a marker for early cardiac involvement in sarcoidosis. Figure 4 shows a case of positive LGE and 18F-FDG PET with FTI evaluation. In this case, regional deformation due to aneurysmal formation was visualized well with FTI.
Figure 4

A man in his 40s was diagnosed as systemic sarcoidosis by transbronchial lung biopsy.

Due to complete right bundle branch block and diffuse left ventricular dysfunction, he was referred for CMR. Left ventricular 2-chamber view of the late gadolinium enhanced CMR shows hyperenhancement at the inferior wall (A, yellow arrows). After a long fast with a low-carbohydrate diet, the 18F-FDG positron emission tomography/computed tomography reveals abnormal FDG uptake at the inferior wall, indicating active cardiac sarcoidosis (B). (C and D) Feature-tracking using cine magnetic resonance imaging for longitudinal strain clearly depicts regional wall motion abnormality with aneurysmal deformation of the mid-inferior wall (green strain curve).
CMR = cardiac magnetic resonance imaging; FDG = fluorodeoxyglucose.
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An autopsy study reported that aneurysm formation was present in 8% of patients with cardiac sarcoidosis,18) the combination of CMR and 18F-FDG PET could help differentiate left ventricular aneurysm due to CS from myocardial infarction.

DIAGNOSTIC ABILITY

Systematic reviews about the diagnostic ability of 18F-FDG PET and CMR are summarized in Tables 4, 5, 6.56)57)58)59)60)61)62)63)64)65)66)67)68)69)70)71)72)73)74)75)76)77)78)79)80)81)82)83)84)85)86)87)88)89)90)91)92)93)94)95)96)97)98)99)100)101)102)103)104)105)106)107)108)109)110)111) The sensitivity of 18F-FDG PET in the diagnosis of CS ranges from 27% to 100%, depending on disease activity since it can only detect active lesions. CMR has a similar sensitivity in detecting CS (range, 28%–100%). Importantly, 18F-FDG PET and CMR provide different aspects of the pathophysiology of CS.108) Therefore, both modalities are recommended for patients who meet the following criteria: (1) equivocal or negative CMR findings in the setting of high clinical suspicion; (2) CMR findings with highly probable CS. In such cases, 18F-FDG PET may identify inflammation/potential role for immunosuppressive therapies. The suggested algorithm for diagnosis is CMR. If LGE is negative, the patient's prognosis would be excellent. However, if LGE is positive or inconclusive, the disease activity should be evaluated using 18F-FDG PET for immunosuppressive therapy.
Table 4

Diagnostic performance of 18F-FDG PET and 18F-FDG PET/CT to detect cardiac involvement in patients with sarcoidosis

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Author Year Countries No. Fasting time (hr) Preparation Quantitative PET interpretation Diagnostic criteria (years) TP (n) FP (n) FN (n) TN (n) Sensitivity (%) Specificity (%)
FDG PET
Yamagishi et al.56) 2003 Japan 17 ≥5 None Yes JMHW (1993) 14 0 3 0 82 -
Okumura et al.57) 2004 Japan 22 ≥12 None Yes JMHW (1993) 11 1 0 10 100 91
Ishimaru et al.36) 2005 Japan 32 ≥6 UFH No JMHW (1993) 5 5 0 22 100 81
Matoh et al.58) 2008 Japan 3 ≥5 None No JMHW (1993) 0 2 0 1 - 33
Ohira et al.59) 2008 Japan 21 ≥6 UFH No JMHW (1993) 7 13 1 5 88 28
Tahara et al.60) 2010 Japan 24 ≥12 None Yes Modified JMHW (2006) 12 1 0 11 100 92
Manabe et al.26) 2013 Japan 50 ≥6 UFH No JMHW (1993) 23 10 1 16 96 62
Manabe et al.61) 2014 Japan 59 ≥6 UFH Yes JMHW (1993) 25 10 2 22 93 69
FDG PET/CT
Langah et al.62) 2009 USA 30 >18 None Yes JMHW (1993) 17 1 3 9 85 90
Youssef et al.63) 2012 Canada 24 ≥12 None Yes Modified JMHW (2006) 11 3 3 7 79 70
Ambrosini et al.64) 2013 Italy 43 >12 HFLC No JMHW (1993) 0 2 3 38 - 95
Mc Ardle et al.65) 2013 Canada 27 ≥12 HFLC No Modified JMHW (2006) 26 0 1 0 96 -
Soussan et al.66) 2013 France 58 ≥4 HFLC No JMHW (1993) 10 10 2 36 83 78
Blankstein et al.3) 2014 USA 112 ≥3 HFLC No JMHW (1993) 16 15 22 59 42 80
Ito et al.37) 2014 Japan 19 >12 UFH No Modified JMHW (2006) 9 0 10 0 47 -
Kobayashi et al.67) 2015 Japan 31 ≥18 None No Modified JMHW (2006) 17 0 14 0 55 -
Momose et al.68) 2015 Japan 52 ≥12 LC+UFH No Modified JMHW (2006) 15 19 0 18 100 49
Orii et al.69) 2015 Japan 32 ≥18 LC+UFH No Modified JMHW (2006) 26 0 6 0 81 -
Simonen et al.70) 2015 Finland 68 ≥12 None No Own criteria 62 0 6 0 91 -
Yokoyama et al.71) 2015 Japan 92 ≥18 LC Yes Modified JMHW (2006) 36 9 1 46 97 84
Gormsen et al.72) 2016 Denmark 19 NA None No JMHW (1993) 1 2 2 14 33 88
Ohira et al.73) 2016 Canada, Japan 30 ≥12 HFLC No Modified JMHW (2006) 24 0 6 0 80 -
Ahmadian et al.74) 2017 USA 17 ≥12 HFLC Yes Modified JMHW (2006) 17 0 0 0 100 -
Lee et al.75) 2017 USA 16 >8 HFLC Yes JMHW (1993) 16 0 0 0 100 -
Norikane et al.76) 2017 Japan 20 >18 None No JSSOG (2015) 11 0 2 7 85 100
Yalagudri et al.77) 2017 India 18 NA NA No HRS (2014) 14 0 4 0 78 -
Furuya et al.78) 2018 Japan 38 ≥18 LC Yes JSSOG (2015) or HRS (2014) 38 0 0 0 100 -
Lebasnier et al.79) 2018 France 30 ≥12 HFLC Yes Modified JMHW (2006) 5 4 1 20 83 83
Varghese et al.80) 2018 USA 154 NA HFLC Yes Modified JMHW (2006) or HRS (2014) 19 33 16 86 54 72
Muser et al.81) 2018 USA 29 ≥18 HFLC+UFH Yes HRS (2014) 14 0 15 0 48 -
Schildt et al.82) 2018 Finland 231 ≥12 None Yes HRS (2014) 23 40 24 141 50 78
Divakaran et al.83) 2019 USA 18 ≥4 HFLC No Explanted heart histology 9 5 0 4 100 44
Furuya et al.84) 2019 Japan 10 ≥18 LC No JSSOG (2015) 9 0 0 1 100 100
Manabe et al.38) 2019 Japan 89 ≥18 LC Yes JSSOG (2015) 35 10 2 42 95 81
Ning et al.34) 2019 USA 34 ≥12 LC No Own criteria 27 0 7 0 79 -
Sgard et al.85) 2019 France 80 NA HFLC No Modified JMHW (2006) 6 5 16 53 27 91
HRS (2014) 11 0 29 40 28 100
Togo et al.86) 2019 Japan 85 ≥18 LC Yes JSSOG (2015) 26 5 7 47 79 90
Zipse et al.87) 2019 USA 72 NA NA No HRS (2014) 49 0 8 15 86 100
Higashi et al.88) 2020 Japan 36 >18 LC No Modified JMHW (2006) 10 4 0 22 100 85
Kawai et al.89) 2020 Japan 94 ≥18 LC No JSSOG (2015) 31 11 3 49 91 82
HRS (2014) 16 26 6 46 73 64
Miller et al.90) 2020 USA 69 ≥8 HFLC Yes Modified JMHW (2006) 24 2 5 38 83 95
Okune et al.91) 2020 Japan 74 ≥18 LC Yes JSSOG (2015) 29 9 11 25 73 74
FDG PET/MR (PET alone)
Wicks et al.92) 2018 UK 51 ≥12 HFLC No Modified JMHW (2006) 20 8 13 10 61 56
CT = computed tomography; FDG = fluorodeoxyglucose; FN = false negative; FP = false-positive; HFLC = high-fat/low-carbohydrate diet; HRS = Heart Rhythm Society; JMHW = Japanese Ministry of Health and Welfare; JSSOG = Japanese Society of Sarcoidosis and Other Granulomatous Disorders; LC = low-carbohydrate; MR = magnetic resonance; NA = not available; PET = positron emission tomography; TN = true negative; TP = true positive; UFH = unfractionated heparin injection.
Table 5

Diagnostic performance of CMR to detect cardiac involvement in patients with sarcoidosis

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Author Year Countries No. Scanner CMR protocol T1/T2 maps Diagnostic criteria (years) TP (n) FP (n) FN (n) TN (n) Sensitivity (%) Specificity (%)
Smedema et al.93) 2005 The Netherlands 88 1.5T Cine, T2WI, LGE None JMHW (1993) 12 12 2 62 86 84
Smedema et al.94) 2005 The Netherlands 58 1.5T Cine, T2WI, LGE None JMHW (1993) 12 10 0 36 100 78
Tadamura et al.95) 2005 Japan 10 1.5T Cine, LGE None JMHW (1993) 10 0 0 0 100 -
Ichinose et al.96) 2008 Japan 30 1.5T Cine, LGE None JMHW (1993) 10 0 1 29 91 100
Matoh et al.58) 2008 Japan 12 1.5T Cine, LGE None JMHW (1993) 2 3 0 7 100 70
Ohira et al.59) 2008 Japan 21 1.5T Cine, LGE, T2WI None JMHW (1993) 6 3 2 10 75 77
Manins et al.97) 2009 Australia 20 1.5T Cine, LGE, T2WI None JMHW (1993) 8 3 0 9 100 75
Patel et al.4) 2009 USA 81 1.5T Cine, LGE None JMHW (1993) 8 13 2 58 80 82
Patel et al.14) 2011 USA 152 1.5T Cine, LGE None JMHW (1993) 14 13 21 102 40 89
Mc Ardle et al.65) 2013 Canada 13 NA LGE None Modified JMHW (2006) 8 0 5 0 62 -
Soussan et al.66) 2013 France 35 1.5T Cine, LGE, T2WI None JMHW (1993) 10 7 0 18 100 72
Watanabe et al.98) 2013 Japan 19 1.5T Cine, LGE None Modified JMHW (2006) 17 0 2 0 89 -
Matsumoto et al.99) 2015 Japan 17 NA LGE NA Modified JMHW (2006) 7 0 0 10 100 100
Momose et al.68) 2015 Japan 27 1.5T or 3.0T Cine, LGE NA Modified JMHW (2006) 6 21 0 0 100 -
Orii et al.69) 2015 Japan 32 1.5T Cine, LGE, T2WI None Modified JMHW (2006) 32 0 0 0 100 -
Simonen et al.70) 2015 Finland 43 NA Cine, LGE None Own criteria 33 0 10 0 77 -
Tezuka et al.100) 2015 Japan 24 1.5T Cine, LGE, T2WI None Modified JMHW (2006) 15 6 0 3 100 33
Yokoyama et al.71) 2015 Japan 69 NA LGE None Modified JMHW (2006) 24 28 2 15 92 35
Komada et al.101) 2016 Japan 9 1.5T Cine, LGE None JMHW (1993) 9 0 0 0 100 -
Ohira et al.73) 2016 Canada, Japan 30 1.5T Cine, LGE None Modified JMHW (2006) 26 0 4 0 87 -
Aikawa et al.102) 2017 Japan 14 1.5T or 3.0T Cine, LGE None JSSOG (2015) 10 3 0 1 100 25
Kataoka et al.103) 2017 Japan 16 1.5T or 3.0T Cine, LGE None Modified JMHW (2006) 7 9 0 0 100 -
Stanton et al.104) 2017 Australia 46 1.5T Cine, LGE, T2WI None Modified JMHW (2006) 2 8 0 36 100 82
Smedema et al.105) 2017 The Netherlands 40 1.5T Cine, LGE None JMHW (1993) 29 0 1 10 97 100
Kouranos et al.106) 2017 Greece 321 1.5T or 3.0T Cine, LGE None HRS (2014) 93 0 3 225 97 100
Yalagudri et al.77) 2017 India 11 NA LGE None HRS (2014) 11 0 0 0 100 -
Ghanizada et al.107) 2018 Denmark 9 NA Cine, LGE, T2WI None JMHW (1993) 9 0 0 0 100 -
Muser et al.81) 2018 USA 29 1.5T Cine, LGE None HRS (2014) 26 0 3 0 90 -
Vita et al.108) 2018 USA 107 3.0T Cine, LGE None HRS (2014) 51 40 6 10 89 20
Wicks et al.92) 2018 UK 51 PET/MR3.0T Cine, LGE None Modified JMHW (2006) 26 6 7 12 79 67
Darlington et al.109) 2019 Sweden 42 1.5T Cine, LGE None HRS (2014) 12 0 0 30 100 100
Divakaran et al.83) 2019 USA 31 3.0T Cine, LGE None Explanted heart histology 1 7 0 23 100 77
Russo et al.110) 2019 Canada 25 NA Cine, LGE None HRS (2014) 10 7 1 7 91 50
Modified JMHW (2006) 8 7 3 7 73 50
Sgard et al.85) 2019 France 80 1.5T Cine, LGE, T2WI None Modified JMHW (2006) 18 16 4 42 82 72
HRS (2014) 34 0 6 40 85 100
Zipse et al.87) 2019 USA 104 NA LGE None HRS (2014) 36 0 25 43 59 100
Kawai et al.89) 2020 Japan 52 NA LGE None JSSOG (2015) 16 16 3 17 84 52
HRS (2014) 9 23 3 17 75 43
Miller et al.90) 2020 USA 69 NA LGE None Modified JMHW (2006) 8 14 21 26 28 65
Okune et al.91) 2020 Japan 74 1.5T Cine, LGE None JSSOG (2015) 39 24 1 10 98 29
Orii et al.111) 2020 Japan 50 1.5T Cine None HRS (2014) 3 1 5 41 38 98
T2WI 6 2 2 40 75 95
LGE 8 10 0 32 100 76
CMR = cardiac magnetic resonance imaging; FN = false negative; FP = false-positive; HRS = Heart Rhythm Society; JMHW = Japanese Ministry of Health and Welfare; JSSOG = Japanese Society of Sarcoidosis and Other Granulomatous Disorders; LGE = late gadolinium enhancement; MR = magnetic resonance; NA = not available; PET = positron emission tomography; T2WI = T2-weighted imaging; TN = true negative; TP = true positive.
Table 6

Diagnostic performance CMR in combination with FDG PET to detect cardiac involvement in patients with sarcoidosis

kcj-51-561-i006
Author Year Countries No. Fasting time CMR scanner CMR protocol Diagnostic criteria (years) TP (n) FP (n) FN (n) TN (n) Sensitivity (%) Specificity (%)
Matoh et al.58) 2008 Japan 3 ≥5 1.5T Cine, LGE JMHW (1993) 2 0 0 1 100 100
Ohira et al.59) 2008 Japan 21 ≥6 1.5T Cine, LGE, T2WI JMHW (1993) 8 8 0 5 100 38
Soussan et al.66) 2013 France 35 ≥4 1.5T Cine, LGE, T2WI JMHW (1993) 10 10 0 15 100 60
Yokoyama et al.71) 2015 Japan 26 ≥18 NA LGE Modified JMHW (2006) 26 0 0 0 100 -
Yalagudri et al.77) 2017 India 11 NA NA LGE HRS (2014) 11 0 0 0 100 -
Wicks et al.92) 2018 UK 51 ≥12 Hybrid PET/MR 3.0T Cine, LGE Modified JMHW (2006) 30 13 3 5 91 28
Divakaran et al.83) 2019 USA 7 ≥4 3.0T Cine, LGE Explanted heart histology 1 3 0 3 100 5
Sgard et al.85) 2019 France 80 NA 1.5T Cine, LGE, T2WI Modified JMHW (2006) 18 18 4 40 82 69
HRS (2014) 36 0 4 40 90 100
Okune et al.91) 2020 Japan 74 ≥18 1.5T Cine, LGE JSSOG (2015) 39 26 1 8 98 24
Orii et al.111) 2020 Japan 50 1.5T 1.5T Cine, T2WI, LGE HRS (2014) 8 10 0 32 100 76
CMR = cardiac magnetic resonance imaging; FDG = fluorodeoxyglucose; FN = false negative; FP = false-positive; HRS = Heart Rhythm Society; JMHW = Japanese Ministry of Health and Welfare; JSSOG = Japanese Society of Sarcoidosis and Other Granulomatous Disorders; LGE = late gadolinium enhancement; MR = magnetic resonance; NA = not available; PET = positron emission tomography; T2WI = T2-weighted imaging; TN = true negative; TP = true positive.

COMPUTED TOMOGRAPHY

The disadvantage of MRI is that it is contraindicated for patients with MR unsafe implantable devices or implantable devices. In patients with non-ischemic cardiomyopathy unable to undergo CMR, cardiac computed tomography (CT) can also be used to perform delayed enhancement imaging.112) CT may be advantageous due to its comprehensive systemic evaluation of sarcoidosis. After whole-body scanning, a delayed cardiac scan could be consequently performed even in patients with implantable devices. We reported that the image quality of delayed iodine contrast-enhanced CT (DE-CT) sufficiently allows for the assessment of hyper-enhanced myocardium in patients with or without implantable devices.102)113) DE-CT can also delineate the extent of CS with an accuracy comparable to that of LGE-CMR. 102)
Figure 5 shows a representative case before and after implantation of a cardioverter-defibrillator following DE-CT. Since the contrast noise ratio of DE-CT was relatively lower than CMR, reader experience is required to visually assess the DE-CT results. As observed in 18F-FDG PET,38) objective texture analysis of myocardial DE-CT showed a similar diagnostic value and higher reproducibility for differentiating between CS and non-CS patients compared to visual assessment.114)
Figure 5

Arrhythmia was detected in a woman in her 50s. Abnormal enhancement and uptake are shown in the left ventricular lateral wall with late gadolinium enhancement of CMR and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (A and B, arrows). DE-CT also highlights the abnormal enhancement in the lateral wall, seen in the CMR (C, arrows). The patient was diagnosed with active cardiac sarcoidosis and was implanted with an ICD to prevent ventricular tachycardia. DE-CT after ICD implantation reveals abnormal enhancement in the lateral wall, as seen previously (D, arrows). Although there were metal artifacts mainly at the septum due to the ICD leads, we were able to compare the 2 images and confirm that the lesion was not worsening over time.

CMR = cardiac magnetic resonance imaging; DE-CT = delayed iodine contrast-enhanced computed tomography; ICD = implantable cardioverter-defibrillator.
kcj-51-561-g005

CONCLUSION

CS remains a morbid and potentially fatal manifestation of sarcoidosis. Though the diagnosis of CS is still challenging, 18F-FDG PET and CMR are promising tools that may help us improve the diagnosis and understanding of the pathophysiology of CS.

Notes

Funding: This study was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI # 20K08042 (NOM), Kondou Kinen Medical Foundation (TA), and Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering (TA).

Conflict of Interest: Dr. Noriko Oyama-Manabe has activities as consultant for Canon Medical Systems; also, she got payment for lectures from Daiichi-Sankyo, Philips Medical Systems, Eisai, Bayer Healthcare, GE Healthcare, Nihon Medi-Physics, Co., Ltd. and Canon Medical Systems.

Data Sharing Statement: The data generated in this study is available from the corresponding authors upon reasonable request.

Author Contributions:

  • Conceptualization: Oyama-Manabe N.

  • Data curation: Oyama-Manabe N, Aikawa T, Tsuneta S.

  • Formal analysis: Oyama-Manabe N, Aikawa T.

  • Funding acquisition: Oyama-Manabe N.

  • Investigation: Oyama-Manabe N, Manabe O.

  • Methodology: Oyama-Manabe N, Manabe O, Aikawa T.

  • Project administration: Oyama-Manabe N, Manabe O, Aikawa T.

  • Resources: Oyama-Manabe N, Manabe O, Aikawa T, Tsuneta S.

  • Software: Manabe O, Aikawa T, Tsuneta S.

  • Supervision: Oyama-Manabe N, Manabe O.

  • Validation: Tsuneta S.

  • Visualization: Aikawa T, Tsuneta S.

  • Writing - original draft: Oyama-Manabe N.

  • Writing - review & editing: Oyama-Manabe N, Manabe O.

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