pISSN 1738-5520 eISSN 1738-5555
Indexed in PubMed, SCIE and Scopus
Open Access, Peer-reviewed, Monthly
    Korean Circ J. 2021 Jul;51(7):561-578. English.
    Published online May 10, 2021.
    https://doi.org/10.4070/kcj.2021.0104
    Copyright © 2021. The Korean Society of Cardiology
    Review

    The Role of Multimodality Imaging in Cardiac Sarcoidosis

    Noriko Oyama-Manabe, MD, PhD,1,* Osamu Manabe, MD, PhD,1,* Tadao Aikawa, MD, PhD,1,2 and 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. Email: norikomanabe@jichi.ac.jp

      *Dr. Noriko Oyama-Manabe and Osamu Manabe equally contributed this article.
    Received March 30, 2021; Accepted April 21, 2021.

    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

    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)

    Table 3
    Heart Rhythm Society's Expert Consensus Statement for diagnosis of CS29)

    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.

    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).

    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).

    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.

    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

    Table 5
    Diagnostic performance of CMR to detect cardiac involvement in patients with sarcoidosis

    Table 6
    Diagnostic performance CMR in combination with FDG PET to detect cardiac involvement in patients with sarcoidosis

    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.

    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.

    References

      1. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–2165.
      1. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:149–173.
      1. Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014;63:329–336.
      1. Patel MR, Cawley PJ, Heitner JF, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation 2009;120:1969–1977.
      1. Costabel U, Hunninghake GW. Sarcoidosis Statement Committee; American Thoracic Society; European Respiratory Society; World Association for Sarcoidosis and Other Granulomatous Disorders. ATS/ERS/WASOG statement on sarcoidosis. Eur Respir J 1999;14:735–737.
      1. Rybicki BA, Iannuzzi MC. Epidemiology of sarcoidosis: recent advances and future prospects. Semin Respir Crit Care Med 2007;28:22–35.
      1. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997;336:1224–1234.
      1. Greulich S, Deluigi CC, Gloekler S, et al. CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imaging 2013;6:501–511.
      1. Blauwet LA, Cooper LT. Idiopathic giant cell myocarditis and cardiac sarcoidosis. Heart Fail Rev 2013;18:733–746.
      1. Dubrey SW, Falk RH. Diagnosis and management of cardiac sarcoidosis. Prog Cardiovasc Dis 2010;52:336–346.
      1. Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:1204–1211.
      1. Iwai K, Tachibana T, Takemura T, Matsui Y, Kitaichi M, Kawabata Y. Pathological studies on sarcoidosis autopsy. I. Epidemiological features of 320 cases in Japan. Acta Pathol Jpn 1993;43:372–376.
      1. Mehta D, Lubitz SA, Frankel Z, et al. Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing. Chest 2008;133:1426–1435.
      1. Patel AR, Klein MR, Chandra S, et al. Myocardial damage in patients with sarcoidosis and preserved left ventricular systolic function: an observational study. Eur J Heart Fail 2011;13:1231–1237.
      1. Vignaux O, Dhote R, Duboc D, et al. Detection of myocardial involvement in patients with sarcoidosis applying T2-weighted, contrast-enhanced, and cine magnetic resonance imaging: initial results of a prospective study. J Comput Assist Tomogr 2002;26:762–767.
      1. Hulten E, Aslam S, Osborne M, Abbasi S, Bittencourt MS, Blankstein R. Cardiac sarcoidosis-state of the art review. Cardiovasc Diagn Ther 2016;6:50–63.
      1. Tavora F, Cresswell N, Li L, Ripple M, Solomon C, Burke A. Comparison of necropsy findings in patients with sarcoidosis dying suddenly from cardiac sarcoidosis versus dying suddenly from other causes. Am J Cardiol 2009;104:571–577.
      1. Roberts WC, McAllister HA Jr, Ferrans VJ. Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med 1977;63:86–108.
      1. Kandolin R, Lehtonen J, Graner M, et al. Diagnosing isolated cardiac sarcoidosis. J Intern Med 2011;270:461–468.
      1. Houston BA, Mukherjee M. Cardiac sarcoidosis: clinical manifestations, imaging characteristics, and therapeutic approach. Clin Med Insights Cardiol 2014;8:31–37.
      1. Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP. Cardiac sarcoidosis: a comprehensive review. Arch Med Sci 2011;7:546–554.
      1. Chapelon-Abric C, de Zuttere D, Duhaut P, et al. Cardiac sarcoidosis: a retrospective study of 41 cases. Medicine (Baltimore) 2004;83:315–334.
      1. Matsui Y, Iwai K, Tachibana T, et al. Clinicopathological study of fatal myocardial sarcoidosis. Ann N Y Acad Sci 1976;278:455–469.
      1. Fleming HA, Bailey SM. Sarcoid heart disease. J R Coll Physicians Lond 1981;15:245–246. 249–253.
      1. Terasaki F, Azuma A, Anzai T, et al. JCS 2016 guideline on diagnosis and treatment of cardiac sarcoidosis - digest version. Circ J 2019;83:2329–2388.
      1. Manabe O, Ohira H, Yoshinaga K, et al. Elevated 18F-fluorodeoxyglucose uptake in the interventricular septum is associated with atrioventricular block in patients with suspected cardiac involvement sarcoidosis. Eur J Nucl Med Mol Imaging 2013;40:1558–1566.
      1. Hiraga H, Iwai K, Hiroe M, Omori F, Sekiguchi M, Tachibana T. In: Guidelines for diagnosis of cardiac sarcoidosis: study report on diffuse pulmonary diseases [in Japanese]. Tokyo: The Japanese Ministry of Health and Welfare; 1993. pp. 23-24.
      1. Diagnostic standard and guidelines for sarcoidosis. Jpn J Sarcoidosis Granulomatous Disord 2007;27:89–102.
      1. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305–1323.
      1. Manabe O, Naya M, Aikawa T, Tamaki N. Recent advances in cardiac positron emission tomography for quantitative perfusion analyses and molecular imaging. Ann Nucl Med 2020;34:697–706.
      1. Manabe O, Yoshinaga K, Ohira H, et al. The effects of 18-h fasting with low-carbohydrate diet preparation on suppressed physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake and possible minimal effects of unfractionated heparin use in patients with suspected cardiac involvement sarcoidosis. J Nucl Cardiol 2016;23:244–252.
      1. Yamada S, Kubota K, Kubota R, Ido T, Tamahashi N. High accumulation of fluorine-18-fluorodeoxyglucose in turpentine-induced inflammatory tissue. J Nucl Med 1995;36:1301–1306.
      1. Mochizuki T, Tsukamoto E, Kuge Y, et al. FDG uptake and glucose transporter subtype expressions in experimental tumor and inflammation models. J Nucl Med 2001;42:1551–1555.
      1. Ning N, Guo HH, Iagaru A, Mittra E, Fowler M, Witteles R. Serial cardiac FDG-PET for the diagnosis and therapeutic guidance of patients with cardiac sarcoidosis. J Card Fail 2019;25:307–311.
      1. Yoshinaga K, Manabe O, Ohira H, Tamaki N. Focus issue on cardiac sarcoidosis from international congress of nuclear cardiology and cardiac CT (ICNC 12) symposium: improving the detectability of cardiac sarcoidosis—practical aspects of 18F-fluorodeoxyglucose positron emission tomography imaging for diagnosis of cardiac sarcoidosis—. Annals of Nuclear Cardiology 2015;1:87–94.
      1. Ishimaru S, Tsujino I, Takei T, et al. Focal uptake on 18F-fluoro-2-deoxyglucose positron emission tomography images indicates cardiac involvement of sarcoidosis. Eur Heart J 2005;26:1538–1543.
      1. Ito K, Okazaki O, Morooka M, Kubota K, Minamimoto R, Hiroe M. Visual findings of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with cardiac sarcoidosis. Intern Med 2014;53:2041–2049.
      1. Manabe O, Ohira H, Hirata K, et al. Use of 18F-FDG PET/CT texture analysis to diagnose cardiac sarcoidosis. Eur J Nucl Med Mol Imaging 2019;46:1240–1247.
      1. Okasha O, Kazmirczak F, Chen KA, Farzaneh-Far A, Shenoy C. Myocardial involvement in patients with histologically diagnosed cardiac sarcoidosis: a systematic review and meta-analysis of gross pathological images from autopsy or cardiac transplantation cases. J Am Heart Assoc 2019;8:e011253
      1. Coleman GC, Shaw PW, Balfour PC Jr, et al. Prognostic value of myocardial scarring on CMR in patients with cardiac sarcoidosis: a systematic review and meta-analysis. JACC Cardiovasc Imaging 2017;10:411–420.
      1. Hulten E, Agarwal V, Cahill M, et al. Presence of late gadolinium enhancement by cardiac magnetic resonance among patients with suspected cardiac sarcoidosis is associated with adverse cardiovascular prognosis: a systematic review and meta-analysis. Circ Cardiovasc Imaging 2016;9:e005001
      1. Tadic M, Cuspidi C, Saeed S, Milojevic B, Milojevic IG. The role of cardiac magnetic resonance in diagnosis of cardiac sarcoidosis. Heart Fail Rev 2021;26:653–660.
      1. Greulich S, Kitterer D, Latus J, et al. Comprehensive cardiovascular magnetic resonance assessment in patients with sarcoidosis and preserved left ventricular ejection fraction. Circ Cardiovasc Imaging 2016;9:e005022.
      1. Puntmann VO, Isted A, Hinojar R, Foote L, Carr-White G, Nagel E. T1 and T2 mapping in recognition of early cardiac involvement in systemic sarcoidosis. Radiology 2017;285:63–72.
      1. Isted A, Grigoratos C, Bratis K, Carr-White G, Nagel E, Puntmann VO. Native T1 in deciphering the reversible myocardial inflammation in cardiac sarcoidosis with anti-inflammatory treatment. Int J Cardiol 2016;203:459–462.
      1. Gorcsan J 3rd, Tanaka H. Echocardiographic assessment of myocardial strain. J Am Coll Cardiol 2011;58:1401–1413.
      1. Barssoum K, Altibi AM, Rai D, et al. Speckle tracking echocardiography can predict subclinical myocardial involvement in patients with sarcoidosis: a meta-analysis. Echocardiography 2020;37:2061–2070.
      1. Kusunose K, Fujiwara M, Yamada H, et al. Deterioration of biventricular strain is an early marker of cardiac involvement in confirmed sarcoidosis. Eur Heart J Cardiovasc Imaging 2020;21:796–804.
      1. Mordi I, Bezerra H, Carrick D, Tzemos N. The combined incremental prognostic value of LVEF, late gadolinium enhancement, and global circumferential strain assessed by CMR. JACC Cardiovasc Imaging 2015;8:540–549.
      1. Korosoglou G, Giusca S, Hofmann NP, et al. Strain-encoded magnetic resonance: a method for the assessment of myocardial deformation. ESC Heart Fail 2019;6:584–602.
      1. Oyama-Manabe N, Ishimori N, Sugimori H, et al. Identification and further differentiation of subendocardial and transmural myocardial infarction by fast strain-encoded (SENC) magnetic resonance imaging at 3.0 Tesla. Eur Radiol 2011;21:2362–2368.
      1. Eitel I, Stiermaier T, Lange T, et al. Cardiac magnetic resonance myocardial feature tracking for optimized prediction of cardiovascular events following myocardial infarction. JACC Cardiovasc Imaging 2018;11:1433–1444.
      1. Nakano S, Kimura F, Osman N, et al. Improved myocardial strain measured by strain-encoded magnetic resonance imaging in a patient with cardiac sarcoidosis. Can J Cardiol 2013;29:1531.e9–1531.11.
      1. Backhaus SJ, Metschies G, Zieschang V, et al. Head-to-head comparison of cardiovascular MR feature tracking cine versus acquisition-based deformation strain imaging using myocardial tagging and strain encoding. Magn Reson Med 2021;85:357–368.
      1. Dabir D, Meyer D, Kuetting D, et al. Diagnostic value of cardiac magnetic resonance strain analysis for detection of cardiac sarcoidosis. RoFo Fortschr Geb Rontgenstr Nuklearmed 2018;190:712–721.
      1. Yamagishi H, Shirai N, Takagi M, et al. Identification of cardiac sarcoidosis with 13N-NH3/18F-FDG PET. J Nucl Med 2003;44:1030–1036.
      1. Okumura W, Iwasaki T, Toyama T, et al. Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis. J Nucl Med 2004;45:1989–1998.
      1. Matoh F, Satoh H, Shiraki K, et al. The usefulness of delayed enhancement magnetic resonance imaging for diagnosis and evaluation of cardiac function in patients with cardiac sarcoidosis. J Cardiol 2008;51:179–188.
      1. Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with 18F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging 2008;35:933–941.
      1. Tahara N, Tahara A, Nitta Y, et al. Heterogeneous myocardial FDG uptake and the disease activity in cardiac sarcoidosis. JACC Cardiovasc Imaging 2010;3:1219–1228.
      1. Manabe O, Yoshinaga K, Ohira H, et al. Right ventricular 18F-FDG uptake is an important indicator for cardiac involvement in patients with suspected cardiac sarcoidosis. Ann Nucl Med 2014;28:656–663.
      1. Langah R, Spicer K, Gebregziabher M, Gordon L. Effectiveness of prolonged fasting 18F-FDG PET-CT in the detection of cardiac sarcoidosis. J Nucl Cardiol 2009;16:801–810.
      1. Youssef G, Leung E, Mylonas I, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012;53:241–248.
      1. Ambrosini V, Zompatori M, Fasano L, et al. 18F-FDG PET/CT for the assessment of disease extension and activity in patients with sarcoidosis: results of a preliminary prospective study. Clin Nucl Med 2013;38:e171–7.
      1. Mc Ardle BA, Birnie DH, Klein R, et al. Is there an association between clinical presentation and the location and extent of myocardial involvement of cardiac sarcoidosis as assessed by 18F- fluorodoexyglucose positron emission tomography? Circ Cardiovasc Imaging 2013;6:617–626.
      1. Soussan M, Brillet PY, Nunes H, et al. Clinical value of a high-fat and low-carbohydrate diet before FDG-PET/CT for evaluation of patients with suspected cardiac sarcoidosis. J Nucl Cardiol 2013;20:120–127.
      1. Kobayashi S, Myoren T, Oda S, et al. Urinary 8-hydroxy-2′-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis. Int J Cardiol 2015;190:319–328.
      1. Momose M, Fukushima K, Kondo C, et al. Diagnosis and detection of myocardial injury in active cardiac sarcoidosis--significance of myocardial fatty acid metabolism and myocardial perfusion mismatch. Circ J 2015;79:2669–2676.
      1. Orii M, Hirata K, Tanimoto T, et al. Comparison of cardiac MRI and 18F-FDG positron emission tomography manifestations and regional response to corticosteroid therapy in newly diagnosed cardiac sarcoidosis with complete heart block. Heart Rhythm 2015;12:2477–2485.
      1. Simonen P, Lehtonen J, Kandolin R, et al. F-18-fluorodeoxyglucose positron emission tomography-guided sampling of mediastinal lymph nodes in the diagnosis of cardiac sarcoidosis. Am J Cardiol 2015;116:1581–1585.
      1. Yokoyama R, Miyagawa M, Okayama H, et al. Quantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis. Int J Cardiol 2015;195:180–187.
      1. Gormsen LC, Haraldsen A, Kramer S, Dias AH, Kim WY, Borghammer P. A dual tracer 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT pilot study for detection of cardiac sarcoidosis. EJNMMI Res 2016;6:52.
      1. Ohira H, Birnie DH, Pena E, et al. Comparison of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) and cardiac magnetic resonance (CMR) in corticosteroid-naive patients with conduction system disease due to cardiac sarcoidosis. Eur J Nucl Med Mol Imaging 2016;43:259–269.
      1. Ahmadian A, Pawar S, Govender P, Berman J, Ruberg FL, Miller EJ. The response of FDG uptake to immunosuppressive treatment on FDG PET/CT imaging for cardiac sarcoidosis. J Nucl Cardiol 2017;24:413–424.
      1. Lee PI, Cheng G, Alavi A. The role of serial FDG PET for assessing therapeutic response in patients with cardiac sarcoidosis. J Nucl Cardiol 2017;24:19–28.
      1. Norikane T, Yamamoto Y, Maeda Y, Noma T, Dobashi H, Nishiyama Y. Comparative evaluation of 18F-FLT and 18F-FDG for detecting cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis. EJNMMI Res 2017;7:69.
      1. Yalagudri S, Zin Thu N, Devidutta S, et al. Tailored approach for management of ventricular tachycardia in cardiac sarcoidosis. J Cardiovasc Electrophysiol 2017;28:893–902.
      1. Furuya S, Manabe O, Ohira H, et al. Which is the proper reference tissue for measuring the change in FDG PET metabolic volume of cardiac sarcoidosis before and after steroid therapy? EJNMMI Res 2018;8:94.
      1. Lebasnier A, Legallois D, Bienvenu B, et al. Diagnostic value of quantitative assessment of cardiac 18F-fluoro-2-deoxyglucose uptake in suspected cardiac sarcoidosis. Ann Nucl Med 2018;32:319–327.
      1. Varghese M, Smiley D, Bellumkonda L, Rosenfeld LE, Zaret B, Miller EJ. Quantitative interpretation of FDG PET for cardiac sarcoidosis reclassifies visually interpreted exams and potentially impacts downstream interventions. Sarcoidosis Vasc Diffuse Lung Dis 2018;35:342–353.
      1. Muser D, Santangeli P, Liang JJ, et al. Characterization of the electroanatomic substrate in cardiac sarcoidosis: correlation with imaging findings of scar and inflammation. JACC Clin Electrophysiol 2018;4:291–303.
      1. Schildt JV, Loimaala AJ, Hippeläinen ET, Ahonen AA. Heterogeneity of myocardial 2-[18F]fluoro-2-deoxy-D-glucose uptake is a typical feature in cardiac sarcoidosis: a study of 231 patients. Eur Heart J Cardiovasc Imaging 2018;19:293–298.
      1. Divakaran S, Stewart GC, Lakdawala NK, et al. Diagnostic accuracy of advanced imaging in cardiac sarcoidosis. Circ Cardiovasc Imaging 2019;12:e008975
      1. Furuya S, Naya M, Manabe O, et al. 18F-FMISO PET/CT detects hypoxic lesions of cardiac and extra-cardiac involvement in patients with sarcoidosis. J Nucl Cardiol. 2019
        [Epub ahead of print].
      1. Sgard B, Brillet PY, Bouvry D, et al. Evaluation of FDG PET combined with cardiac MRI for the diagnosis and therapeutic monitoring of cardiac sarcoidosis. Clin Radiol 2019;74:81.e9–81.18.
      1. Togo R, Hirata K, Manabe O, et al. Cardiac sarcoidosis classification with deep convolutional neural network-based features using polar maps. Comput Biol Med 2019;104:81–86.
      1. Zipse MM, Tzou WS, Schuller JL, et al. Electrophysiologic testing for diagnostic evaluation and risk stratification in patients with suspected cardiac sarcoidosis with preserved left and right ventricular systolic function. J Cardiovasc Electrophysiol 2019;30:1939–1948.
      1. Higashi H, Inaba S, Iio C, et al. Features and clinical impact of extra-cardiac lesions with 18F-fluorodeoxyglucose positron emission tomography in patients with suspected cardiac sarcoidosis. Int J Cardiol Heart Vasc 2020;30:100587
      1. Kawai H, Sarai M, Kato Y, et al. Diagnosis of isolated cardiac sarcoidosis based on new guidelines. ESC Heart Fail 2020;7:2662–2671.
      1. Miller RJ, Cadet S, Pournazari P, et al. Quantitative assessment of cardiac hypermetabolism and perfusion for diagnosis of cardiac sarcoidosis. J Nucl Cardiol. 2020
        [Epub ahead of print].
      1. Okune M, Yasuda M, Soejima N, et al. Diagnostic utility of fusion 18F-fluorodeoxyglucose positron emission tomography/cardiac magnetic resonance imaging in cardiac sarcoidosis. J Nucl Cardiol. 2020
      1. Wicks EC, Menezes LJ, Barnes A, et al. Diagnostic accuracy and prognostic value of simultaneous hybrid 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging in cardiac sarcoidosis. Eur Heart J Cardiovasc Imaging 2018;19:757–767.
      1. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Cardiac involvement in patients with pulmonary sarcoidosis assessed at two university medical centers in the Netherlands. Chest 2005;128:30–35.
      1. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis. J Am Coll Cardiol 2005;45:1683–1690.
      1. Tadamura E, Yamamuro M, Kubo S, et al. Effectiveness of delayed enhanced MRI for identification of cardiac sarcoidosis: comparison with radionuclide imaging. AJR Am J Roentgenol 2005;185:110–115.
      1. Ichinose A, Otani H, Oikawa M, et al. MRI of cardiac sarcoidosis: basal and subepicardial localization of myocardial lesions and their effect on left ventricular function. AJR Am J Roentgenol 2008;191:862–869.
      1. Manins V, Habersberger J, Pfluger H, Taylor AJ. Cardiac magnetic resonance imaging in the evaluation of cardiac sarcoidosis: an Australian single-centre experience. Intern Med J 2009;39:77–82.
      1. Watanabe E, Kimura F, Nakajima T, et al. Late gadolinium enhancement in cardiac sarcoidosis: characteristic magnetic resonance findings and relationship with left ventricular function. J Thorac Imaging 2013;28:60–66.
      1. Matsumoto K, Ehara S, Sakaguchi M, et al. Clinical characteristics of late gadolinium enhancement in patients with cardiac sarcoidosis. Osaka City Med J 2015;61:9–17.
      1. Tezuka D, Terashima M, Kato Y, et al. Clinical characteristics of definite or suspected isolated cardiac sarcoidosis: application of cardiac magnetic resonance imaging and 18F-fluoro-2-deoxyglucose positron-emission tomography/computerized tomography. J Card Fail 2015;21:313–322.
      1. Komada T, Suzuki K, Ishiguchi H, et al. Magnetic resonance imaging of cardiac sarcoidosis: an evaluation of the cardiac segments and layers that exhibit late gadolinium enhancement. Nagoya J Med Sci 2016;78:437–446.
      1. Aikawa T, Oyama-Manabe N, Naya M, et al. Delayed contrast-enhanced computed tomography in patients with known or suspected cardiac sarcoidosis: a feasibility study. Eur Radiol 2017;27:4054–4063.
      1. Kataoka S, Momose M, Fukushima K, et al. Regional myocardial damage and active inflammation in patients with cardiac sarcoidosis detected by non-invasive multi-modal imaging. Ann Nucl Med 2017;31:135–143.
      1. Stanton KM, Ganigara M, Corte P, et al. The utility of cardiac magnetic resonance imaging in the diagnosis of cardiac sarcoidosis. Heart Lung Circ 2017;26:1191–1199.
      1. Smedema JP, van Geuns RJ, Truter R, Mayosi BM, Crijns HJ. Contrast-enhanced cardiac Magnetic Resonance: distinction between cardiac sarcoidosis and infarction scar. Sarcoidosis Vasc Diffuse Lung Dis 2017;34:307–314.
      1. Kouranos V, Tzelepis GE, Rapti A, et al. Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis. JACC Cardiovasc Imaging 2017;10:1437–1447.
      1. Ghanizada M, Rossing K, Bundgaard H, Gustafsson F. Clinical presentation, management and prognosis of patients with cardiac sarcoidosis. Dan Med J 2018;65:A5462.
      1. Vita T, Okada DR, Veillet-Chowdhury M, et al. Complementary value of cardiac magnetic resonance imaging and positron emission tomography/computed tomography in the assessment of cardiac sarcoidosis. Circ Cardiovasc Imaging 2018;11:e007030
      1. Darlington P, Gabrielsen A, Cederlund K, et al. Diagnostic approach for cardiac involvement in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2019;36:11–17.
      1. Russo JJ, Nery PB, Ha AC, et al. Sensitivity and specificity of chest imaging for sarcoidosis screening in patients with cardiac presentations. Sarcoidosis Vasc Diffuse Lung Dis 2019;36:18–24.
      1. Orii M, Tanimoto T, Ota S, et al. Diagnostic accuracy of cardiac magnetic resonance imaging for cardiac sarcoidosis in complete heart block patients implanted with magnetic resonance-conditional pacemaker. J Cardiol 2020;76:191–197.
      1. Narula J, Chandrashekhar Y, Ahmadi A, et al. SCCT 2021 expert consensus document on coronary computed tomographic angiography: a report of the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr 2020:S1934-5925(20)30473-1.
      1. Aikawa T, Koyanagawa K, Oyama-Manabe N, et al. Cardiac sarcoidosis mimicking myocardial infarction: a comprehensive evaluation using computed tomography and positron emission tomography. J Nucl Cardiol 2020;27:1066–1067.
      1. Tsuneta S, Oyama-Manabe N, Hirata K, et al. Texture analysis of delayed contrast-enhanced computed tomography to diagnose cardiac sarcoidosis. Jpn J Radiol 2021;39:442–450.
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    MeSH Terms
    Arrhythmias, Cardiac
    Cardiac Imaging Techniques
    Granuloma
    Heart Failure
    Humans
    Inflammation
    Magnetic Resonance Imaging
    Positron-Emission Tomography
    Positron-Emission Tomography and Computed Tomography
    Prognosis
    Sarcoidosis*
    Tachycardia, Ventricular
    Metrics
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