Sarcoidosis is a multi-factorial inflammatory disease characterised by the formation of non-caseating granulomas in the affected organs. Cardiac involvement can be the first, and occasionally the only, manifestation of sarcoidosis. The prevalence of cardiac sarcoidosis (CS) is higher than previously suspected. CS is associated with increased morbidity and mortality. Thus, early diagnosis is critical to introducing immunosuppressive therapy that could prevent an adverse outcome. Endomyocardial biopsy (EMB) has limited utility in the diagnostic pathway of patients with suspected CS. As a result, advanced imaging modalities, i.e. cardiac magnetic resonance imaging (MRI) and positron emission tomography with 18F-Fluorodeoxyglucose/computed tomography scan (18F-FDG-PET/CT), have emerged as alternative tools for diagnosing CS and might be considered the new ‘gold standard’. This focused review will discuss the epidemiology and pathology of CS, when to suspect and evaluate CS, highlight the complementary roles of cardiac MRI and 18F-FDG-PET/CT, and their diagnostic and prognostic values in CS, in the current content of guidelines for the diagnostic workflow of CS.
Introduction
Cardiac sarcoidosis (CS) is associated with increased morbidity and mortality.1 Thus, early diagnosis is crucial to introducing immunosuppressive therapy that could prevent an adverse outcome.2 This focused review will discuss the pathology of CS, when to suspect and evaluate CS, and highlight the roles of advanced imaging modalities, i.e. cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) with 18F-Fluorodeoxyglucose/computed tomography (CT) scan (18F-FDG-PET/CT), and their diagnostic and prognostic values in CS in the current content of guidelines for the diagnostic workflow of CS.3
Epidemiology and clinical presentation
CS occurs in less than 5% of patients with clinically manifested pulmonary/systemic sarcoidosis.4 However, 27% of autopsied sarcoidosis patients from the US had cardiac involvement.5 The prevalence was as high as 39% in sarcoidosis patients with symptoms (palpitations, pre-syncope, or syncope) or abnormal results (electrocardiogram [ECG], Holter monitoring, and transthoracic echocardiography [TTE]) when studied with cardiac MRI or PET.6
Cardiac involvement may range from silent myocardial granulomas to symptomatic conduction disturbances, ventricular arrhythmias, progressive heart failure and sudden cardiac death (SCD).7
Histopathology
The histological hallmark of sarcoidosis is the formation of non-caseating epithelioid granulomas in the affected organs.8 Sarcoid granuloma consists of a central core surrounded by mainly CD4+ T lymphocytes. The core includes macrophages and multi-nucleate giant cells, which are fused macrophages surrounded by large macrophages called epithelioid cells.9
At an early stage, lymphocyte numbers are noticeable, but the numbers decline with disease progression. The granuloma/fibrosis preferentially affects the sub-epicardial portion of the left ventricular (LV) free wall, followed by the basal interventricular septum and the right ventricle.10 Autopsy of SCD cases due to undiagnosed CS showed the co-presence of dense fibrosis and lymphocytic infiltration in most cases.11
Diagnostic approach
The overall diagnostic yield of endomyocardial biopsy (EMB) is low.12 Also, EMB is not suitable for therapy monitoring.13 As a result, cardiac MRI and 18F-FDG-PET/CT have emerged as alternative tools for diagnosing CS, and might be considered the new ‘gold standard’.
It is advisable to screen all patients with extracardiac sarcoidosis with an ECG14 and TTE with longitudinal strain analysis15 (figure 1). Conduction abnormalities are associated with increased SCD.16 In addition, patients with abnormal ECG or cardiac symptoms (e.g. palpitations, pre-syncope, syncope) should receive further diagnostic testing, i.e. serum N-terminal of the prohormone brain natriuretic peptide (NT-proBNP),17 high-sensitivity cardiac troponin T (hs-cTnT),18 ambulatory ECG monitoring,19 cardiac MRI,20 and 18F-FDG-PET/CT21 (figure 2). Limited data suggest that early immunosuppressive treatment (<1 month from diagnosis) could be associated with a better outcome.22 Therefore, an early investigational work-up is warranted.
TTE features suggestive of CS include regional wall motion abnormality, wall aneurysm, basal septum wall thinning, reduced left ventricular ejection fraction (LVEF) <50%, and abnormal longitudinal strain.19 In addition, the TTE sensitivity and specificity for the diagnosis of CS were 10–47% and 82–92%, respectively.3 Thus, the primary role of TTE is to determine and follow LV function.3
Cardiac MRI (CMR)
The main strength of cardiac MRI in diagnosing CS is identifying patchy foci of late gadolinium enhancement (LGE) in the myocardium.23 The distribution of the LGE foci is usually sub-epicardial or mid-myocardial (non-ischaemic pattern) and along the right ventricular insertion points.24 In addition, the presence of LGE is associated with increased all-cause mortality and ventricular arrhythmia in CS.25
Gadolinium is an extracellular contrast agent with a rapid washout from normal areas of the normal myocardium. However, scar or extracellular expansion due to inflammation can expand the extracellular space and result in a slower washout of gadolinium, leading to increased T1-signal enhancement. A common error is that LGE always means an irreversible scar.12 Therefore, LGE alone is insufficient to distinguish between active and non-active disease (figure 3).26 T2-weighted imaging can detect oedema/inflammation but suffers from low sensitivity due to low signal-to-noise ratio and artefacts.3 The overall sensitivity and specificity of CMR-LGE for diagnosing CS were 93% and 85%, respectively.27
18F-FDG-PET/CT scanning
Proper patient preparation is critical to suppress myocardial glucose uptake and better visualise 18F-FDG uptake in the affected myocardium, i.e. prolonged fasting, high-fat, low-carbohydrate diet, and possibly intravenous heparin administration.28 Therefore, 18F-FDG-PET should be performed at experienced centres.29 The overall sensitivity and specificity of 18F-FDG-PET or PET/CT were 84% and 83%, respectively, but with significant heterogeneity of the included studies, most likely due to the preparation protocols used.30 Abnormal 18F-FDG-PET finding was associated with an increased risk of major adverse cardiovascular events (MACE).31
Furthermore, 18F-FDG-PET has a critical role in serial monitoring of patients during therapy to identify responders and non-responders, in order to filter out the patients who may benefit from immunosuppressive intensification or tapering (figure 3).32 Further, a decrease in 18F-FDG uptake was significantly associated with fewer MACE at long-term follow-up.33
Limited data exist on the timing of serial follow-up in patients with positive 18F-FDG-PET/CT scan. Still, a few studies and case reports showed that an early response after three months of the initiation of the immunosuppressive therapy could be observed.34 Therefore, serial imaging at three, six, and 12 months seems reasonable. The main disadvantage of 18F-FDG-PET/CT is the relatively high cost, radiation exposure, and 10% to 15% of 18F-FDG-PET scans will be inconclusive.28
18F-FDG-PET/CT versus CMR, or both
The pros and cons of CMR and 18F-FDG-PET/CT are summarised in table 1.
Table 1. Comparison between cardiac magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT)
| Cardiac MRI | 18F-FDG-PET/CT | |
|---|---|---|
| Availability | +++ | + |
| Cost | ++ | +++ |
| Requirement for specific preparation | – | +++ |
| Sensitivity and specificity | +++ | ++ |
| Radiation exposure | – | + |
| Cardiac morphology and function | +++ | – |
| Detecting active inflammation | (–/+): with oedema sequence (T2 weighted), but unreliable (++): only reliable with T2 mapping, but more studies are needed |
+++ |
| Detecting extracardiac activity | +++ | |
| Assessment of treatment response | (+): only reliable with T2 mapping, but more studies are needed | +++ |
| eGFR ≤30 ml/min/1.73 m2 | (–): contraindicated (++): native T1 and T2 mapping can still be used |
+++ |
| Patients with implantable cardiac devices | ++ | +++ |
| Prognostic value | +++ | +++ |
| Non-diagnostic result | Rare | In approx. 10% to 15% of scans |
| Key: eGFR = estimated glomerular filtration rate | ||
Considering that LGE cannot distinguish between active and non-active disease,35 18F-FDG-PET/CT is better in detecting the active phase of CS, and allows the clinician to decide on the initiation of immunosuppressive treatment (figure 3).3,21 Additionally, it is also better in identifying extracardiac activity (figure 3), which is present in 97% of patients with CS, and providing a biopsy target.36 Thus, 18F-FDG-PET/CT is the method of choice to monitor and modify immunosuppressive therapy in CS (figure 3).3 Furthermore, 18F-FDG-PET/CT can be utilised in patients with severely reduced chronic kidney disease, and it is the preferred scan in patients with implantable cardiac devices.3 On the other hand, CMR is widely available, with higher sensitivity and negative predictive value, and the presence and extent of LGE have crucial prognostic implications.3,37,38
The European Society of Cardiology (ESC) and the American Thoracic Society (ATS) recommend performing CMR before 18F-FDG-PET scan in patients with suspected cardiac involvement. However, both societies emphasised the complementary value of these tests to increase diagnostic yield and assess for fibrosis and inflammation.3,20
Conclusion
The diagnostic approach in patients with clinically suspected CS should include the cardiac serum markers (NT-proBNP and hs-cTnT), ECG, ambulatory ECG monitoring, TTE with longitudinal strain analysis, and cardiac MRI. If cardiac MRI findings are normal and the clinical suspicion of CS is low, no further imaging is recommended. On the other hand, if cardiac MRI is abnormal or the clinical suspicion is high despite normal MRI results, then 18F-FDG-PET/CT should be utilised. If 18F-FDG-PET/CT is diagnostic and positive, then immunosuppressive treatment is indicated, and a repeat 18F-FDG-PET/CT scan can be considered after three, six, and 12 months to monitor and tailor the immunosuppressive therapy (figure 2).
Key messages
- Cardiac magnetic resonance tomography with late gadolinium enhancement (CMR-LGE) has an excellent negative predictive value to exclude prognostically significant cardiac involvement in suspected cardiac sarcoidosis (CS). However, CMR-LGE alone cannot distinguish between active and non-active disease
- Positron emission tomography with 18F-fluorodeoxyglucose/computed tomography scan (18F-FDG-PET/CT) is better in detecting the active phase of CS
- 18F-FDG-PET/CT is the method of choice to monitor and modify immunosuppressive therapy in CS. Serial follow-up at three, six, and 12 months is reasonable
- 18F-FDG-PET/CT should be performed at experienced centres. Proper patient preparation is critical to suppress myocardial glucose uptake and better visualise 18F-FDG uptake in the affected myocardium
Conflicts of interest
None declared.
Funding
None.
Patient consent
Informed written patient consent for publication has been obtained from the patient described in figure 3.
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