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Curr Cardiol Rep. 2013 April ; 15(4): 352.

18F-FDG PET/CT for the Assessment of Myocardial Sarcoidosis

Hicham Skali,
Department of Radiology, Division of Nuclear Medicine and Molecular imaging, 70 Francis Street,
Shapiro 5th Floor, Room 128, Boston, MA 02115, USA; Department of Medicine, Cardiovascular
Division, 70 Francis Street, Shapiro 5th Floor, Room 128, Boston, MA 02115, USA

Allison R. Schulman, and

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 70 Francis
Street, Shapiro 5th Floor, Room 128, Boston, MA 02115, USA

Sharmila Dorbala
Department of Radiology, Division of Nuclear Medicine and Molecular imaging, 70 Francis Street,
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Shapiro 5th Floor, Room 128, Boston, MA 02115, USA; Department of Medicine, Cardiovascular
Division, 70 Francis Street, Shapiro 5th Floor, Room 128, Boston, MA 02115, USA

Abstract
Cardiac involvement portends a poor prognosis in patients with sarcoidosis. However, due to the
nonspecific clinical manifestations of the disease, patchy myocardial involvement, and the limited
diagnostic yield of diagnostic tests, early diagnosis of cardiac sarcoidosis has been exceedingly
difficult. As a result, there is no standardized approach for the early diagnosis of cardiac
sarcoidosis. Imaging modalities that can both identify disease and predict response to therapy are
paramount to improve management of cardiac sarcoidosis. 18F-FDG PET has many practical
advantages in assessing disease activity and monitoring treatment response in patients with cardiac
sarcoidosis. Accumulating data support the growing role of 18F-fluorodeoxyglucose (18F-FDG)
PET in the diagnosis and risk stratification of patients with cardiac sarcoidosis.

Keywords
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Cardiac sarcoidosis; 18F-FDG; PET; Myocardial sarcoidosis

Introduction
In the United States, cardiac sarcoidosis (CS) represents the cause of death in as many as 13
% to 25 % of fatal cases of sarcoidosis [1]. Although cardiac involvement portends a higher
risk of mortality and morbidity [2], ante-mortem diagnosis of CS remains challenging based
on a broad and nonspecific set of signs and symptoms ranging from asymptomatic
electrocardiographic findings to sudden death and progressively worsening heart failure and

© Springer Science+Business Media New York 2013

S. Dorbala sdorbala@partners.org.
Conflicts of Interest Hicham Skali declares that he has no conflict of interest.
Allison R. Schulman declares that she has no conflict of interest.
 Skali et al. Page 2

arrhythmias [3, 4, 5•, 6••]. Indeed, approximately 25 % of all patients with sarcoidosis have
clinical manifestations of cardiac involvement whereas myocardial granulomas can be
identified in almost 25%–79% of autopsy examinations [7]. Traditionally, the Japanese
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Ministry of Health and Welfare Guidelines (Japanese Ministry Guidelines), published 20

years ago [8], and revised more recently [9••, 10], have attempted to provide diagnosis
criteria that yield a “histologic diagnosis” or “clinical diagnosis” (Table 1). A positive
endomyocardial biopsy can clinch the histologic diagnosis of CS. However, this procedure
carries risks and lacks sensitivity (19 % sensitivity) [11, 12] given the heterogeneous
myocardial involvement [4, 13]. Recently, imaging with positron emission tomography
(PET) using 18F-fluorodeoxyglucose (18F-FDG) has gained momentum in the management
of patients with CS [14, 15]. In this review we detail the technical aspects of 18F-FDG PET
imaging and discuss its role in the clinical diagnosis, assessment of disease activity,
monitoring therapeutic response, and assessment of prognosis for myocardial sarcoidosis.

Pathophysiology and Presentation

The basic pathophysiological abnormality in sarcoidosis is the accumulation of noncaseating
granulomas comprised of organized collections of macrophages, epithelioid cells, and
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lymphocytes [16••]. These granulomas may initially form to encircle the inciting pathogen
such as infectious (mycobacterium or corynebacterium species) or environmental agents
(aluminum, talk, pollen, moldy environments, insecticides, inorganic particles) to protect the
surrounding tissue from damage [16••, 17]. In the process, CD4+ T-cells are activated
leading to inflammation through release of interferon-γ (INF-γ) or interleukin-2 (IL-2).
Tissue scarring may result through a shift in cytokine production from interleukin-2 (IL-2)
and interferon-γ (INF-γ) to interleukins 4, 10, and 13 (IL-4, 10, 13) [16••].

In the heart the granulomas may involve the pericardium, myocardium, and endocardium of
both the ventricles as well as the atria [17]. The myocardium of the left ventricular free wall,
particularly at the base of the heart, is most commonly affected, followed by the basal
interventricular septum. Also, there appears to be a predilection for involvement of the
conduction system.

Cardiac sarcoidosis clinical manifestations relate primarily to the location and inflammatory
effects of the granulomas [16••]. The presence of the granulomas in the ventricular
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myocardium may lead to abnormal automaticity and re-entrant tachyarrhythmias

manifesting as palpitations or syncope. Involvement of the conduction system may lead to
bradyarrhythmias and syncope. Congestive heart failure may result from widespread
sarcoidosis of the myocardium with a decline in left ventricular ejection fraction (EF) and
death. Unlike with other infiltrative cardiomyopathies such as amyloidosis, myocardial
involvement in sarcoidosis is typically patchy. This may account for the low yield from right
ventricular endomyocardial biopsy, which is typically a blind procedure with sampling of
the right ventricular aspect of the interventricular septum. Due to the challenges in
histological diagnosis from endomyocardial biopsy, imaging plays a critical role in the
diagnosis of CS.

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Imaging of Myocardial Inflammation

Several radionuclide techniques are available to image inflammation [18] using 18F-
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FDG, 99mTechnetium (99mTc), or 111Indium (111In) labeled white blood cells, 99mTc
bisphosphonates, 67Gallium-citrate, 99mTc nanocolloids, and 99mTc or 111In labeled proteins
(IgG, albumin). 67Gallium-citrate imaging has low sensitivity and limited spatial resolution
for the detection of sarcoidosis in the extrapulmonary locations, compared with 18F-FDG
PET [19]. Hence, 18F-FDG PET imaging is most commonly used for imaging myocardial
inflammation in clinical practice. The cellular uptake of 18F-FDG in sarcoidosis is related to
these inflammatory cell infiltrates [20–22]. Active inflammatory cells have high glycolytic
activity to satisfy their large energy demands [23], and as a result can produce ATP levels
that are almost 8-fold higher than baseline [24]. After crossing the cellular membrane via
glucose transporters, both 18F-FDG and glucose are phosphorylated by the enzyme
hexokinase. While glucose is further metabolized, the phosphorylated 18F-FDG remains
trapped within the cells and can be imaged [25, 26]. As 18F-FDG accumulates in active
lesions where inflammatory cells utilize glucose as an energy source, active sarcoid lesions
in various organs are visualized by increased 18F-FDG uptake on PET imaging.

Typical radionuclide protocols for imaging cardiac sarcoidosis include 18F-FDG PET for
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imaging inflammation combined with SPECT or PET myocardial perfusion imaging (Fig.
1).

18F-FDG PET: Technical Details

Patient Preparation
Since normal myocytes utilize glucose as one of their main energy sources, various
techniques have been developed to suppress physiological 18F-FDG uptake in the heart and
minimize false-positive results. In this regard, 3 approaches have been tried: prolonged
fasting, dietary modification, and intravenous administration of unfractionated heparin.

In the fasting state, free fatty acids account for up to 90 % of oxygen consumption of normal
myocytes. However, in the post-prandial state, when plasma glucose and insulin levels are
increased, glucose can actually become the dominant source of energy. As a result, fasting
imaging is preferable over post-prandial imaging, in order to decrease physiologic uptake by
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normal myocytes and optimize 18F-FDG PET imaging [14, 20, 21]. While many studies
have been conducted with 5–12 hours of fasting, more recent studies suggest that waiting
more than 18 hours further suppresses physiologic myocardial glucose uptake and may be
preferable [27, 28]. However, fasting imaging remains limited by variable suppression of
glucose utilization by normal myocytes.

Dietary modifications with a high-fat, high-protein, low-carbohydrate diet have been shown
to reduce glucose uptake by normal myocardium [29••, 30]. More recently, low-
carbohydrate diet followed by extended fasting have been studied, and shown to achieve
significant reduction in physiologic uptake [31]. The idea is to shift myocardial metabolism
to fatty acid and suppress glucose utilization and 18F-FDG uptake by the normal
myocardium.

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Finally, some protocols utilize pre-administration of unfractionated intravenous (IV) heparin

for suppressing myocardial 18F-FDG uptake. IV unfractionated heparin activates lipoprotein
and hepatic lipases, thereby increasing plasma free fatty acid levels, and ultimately causing a
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reduction in glucose consumption of normal myocytes. Doses as high as 50 IU/Kg were

used in prior studies [19, 20] without describing any bleeding complications; it remains
unclear whether lower heparin dosing could result in optimal quality imaging [20].

Although not formally tested, it is possible that a combination of all of the above techniques,
ie, high-fat low carbohydrate diet for 2 meals followed by prolonged fasting as well as the
use of intravenous unfractionated heparin may be superior to either one technique alone.

18F-FDG Imaging Protocol

Following the dietary preparation mentioned above, patients receive 10–12 milli Curies
of 18F-FDG intravenously. 18F-FDG PET imaging is begun after an uptake period of 90
minutes during which patients are asked to rest quietly (not talk or engage in physical
activity) (Fig. 1). The heart position is localized with a scout image (CT or radionuclide) and
a transmission scan (CT or radionuclide) is obtained for the measurement and correction of
soft tissue attenuation followed by a non-gated cardiac 18F-FDG image acquisition (2D or
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3D mode). Then, a limited whole body scan is obtained from the base of the skull to mid-
thigh along with a transmission scan for attenuation correction. The cardiac and whole body
images emission images are reconstructed with and without attenuation correction.

Myocardial Perfusion Imaging Protocol

All patients scheduled for 18F-FDG PET for cardiac sarcoidosis should also undergo
myocardial perfusion assessment with 99m Tc, 201Thallium,13N-ammonia, or 82Rubidium
based radiotracers using standard protocols [32, 33]. Attenuation correction should be used
with SPECT myocardial perfusion imaging whenever possible. We recommend perfusion
assessment both at the initial diagnosis and for the follow-up evaluations to assess response
to therapy. Comparison of the perfusion images with 18F-FDG PET images will allow for
differentiation of scar tissue from normal myocardium or change of active sarcoid
granuloma to normal myocardium or progression to scar tissue in response to therapy. It is
also important to exclude epicardial coronary artery disease in these patients with either
invasive or CT based coronary angiography, since patterns of perfusion metabolism
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mismatch in patients with left ventricular systolic dysfunction may reflect either hibernating
myocardium or myocardial inflammation based on the clinical context.

Interpretation of the Perfusion and 18F-FDG PET Images

The perfusion and 18F-FDG PET images are interpreted side-by-side using conventional
cardiac display software and a semi-quantitative visual interpretation. Several descriptions
have been used for 18F-FDG uptake, but, not yet validated with histological disease stage.
One description on the 18F-FDG PET images is: no uptake, diffuse uptake, focal uptake, and
focal on diffuse uptake [9••]. Other investigators have used patterns incorporating
information from the perfusion and information from the 18F-FDG PET images: both normal
perfusion and normal 18F-FDG, either abnormal perfusion or abnormal 18F-FDG, or both
abnormal perfusion and abnormal 18F-FDG [34]. Yet another way to describe the patterns is

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based on a comparison of the degree of perfusion abnormality and 18F-FDG uptake as:
normal (normal perfusion/normal 18F-FDG), early stage (mild perfusion defect/
increased 18F-FDG), progressive stage (moderate perfusion defect/increased 18F-FDG),
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progressive myocardial impairment stage (severe perfusion defect/increased 18F-FDG), and

fibrosis stage (severe perfusion defect/minimal or no 18F-FDG uptake) [21]. These patterns
are summarized in Fig. 2. These stages can be helpful not only in the initial diagnosis, but,
also in follow-up of patients who return for assessment of response to therapy.

For assessment of response to therapy several investigators have relied on the specific
uptake values (SUV) of 18F-FDG to monitor response to therapy [21]. Specific uptake
values represent the decay corrected uptake in the tissue divided by the injected dose of
radiotracer adjusted to body weight [35]. The ratio of SUV values in the myocardium to the
SUV values in other organs, such as cerebellum, has also been used. Others have relied on
the measure of coefficient of variation of the SUV value as a metric to assess response to
therapy [9••]. The clinical value of these SUV metrics to assess disease activity level at
baseline and to assess changes in response to therapy is not well established and needs to
standardized and prospectively validated.

The whole body 18F-FDG PET as well as the CT transmission (on hybrid scanners) images
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need to be reviewed and reported in conjunction with a physician credentialed to supervise

and interpret body PET/CT. Findings supporting a diagnosis of extra-cardiac sarcoid disease
activity or findings to guide a biopsy from an extracardiac location of 18F-FDG uptake (18F-
FDG avid lymph nodes accessible to guided biopsy) as well as incidental diagnosis of
malignancy should be considered.

Role of 18F-FDG PET in the Initial Diagnosis of Myocardial Sarcoidosis

The early diagnosis of cardiac sarcoidosis is imperative, as data suggest that high dose
steroid therapy should be administered to patients with active inflammation before left
ventricular systolic function declines [3, 36, 37]. The traditional approach of reserving
steroids for patients with LVEF <50 %, advanced atrioventricular block, ventricular
tachycardia, or positive cardiac biopsy led to high mortality risk [38, 39]. It is therefore
suspected that there is a tipping point of steroid efficacy where responsive active
granulomatous inflammation/infiltration transforms toward non-responsive fibrosis [40••].
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Several recent studies have demonstrated the promising potential of using PET with 18F-
FDG in the early diagnosis and assessment of cardiac sarcoidosis (Table 2). Yamagishi et al.
[14] enrolled 17 patients with pathology proven systemic sarcoidosis and cardiac
involvement based on the Japanese Ministry Guidelines, and compared 13N-ammonia/18F-
FDG PET imaging vs 67Gallium and 201Thallium scintigraphy. They showed that 18F-FDG
accumulates in patients with cardiac sarcoidosis, similar to what has been observed in
patients with pulmonary involvement. Fifteen patients demonstrated increased
myocardial 18F-FDG uptake, whereas only 6 patients demonstrated defects on 201Thallium
scintigraphy, and only 3 patients showed 67Gallium uptake. Other investigators have
similarly demonstrated higher sensitivity of 18F-FDG PET imaging compared
with 67Gallium or 99mTechnetium sestamibi scintigraphy [20, 27]. Some even suggested

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that 18F-FDG PET can detect early stages of cardiac sarcoidosis where fewer perfusion
abnormalities and less inflammatory activity are noted [21].
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In one of the first studies comparing 18F-FDG PET with cardiac magnetic resonance
imaging (CMR) [41] for the diagnosis of cardiac sarcoid, 21 patients with suspected cardiac
sarcoidosis underwent both CMR and 18F-FDG within 4 weeks. Using the Japanese
Ministry Criteria as the gold standard, 8 of 21 patients were diagnosed with cardiac
sarcoidosis yielding a sensitivity and specificity for 18F-FDG PET of 87.5 % and 38.5 %,
respectively, compared with 75 % and 76.9 % for CMR. A second study by Mehta et al. [23]
similarly showed higher sensitivity for 18F-FDG PET (86 %) than for CMR (36 %) in
patients with suspected cardiac sarcoid.

Many studies have shown that 18F-FDG has a characteristic heterogeneous uptake pattern in
the myocardium in patients with cardiac sarcoidosis [14, 20, 21]. This appearance, as
opposed to the diffuse uptake seen in dilated cardiomyopathy and normal subjects, should
theoretically help distinguish patients with cardiac sarcoidosis and decrease false positive
rates. Tahara et al. [9••] compared the quantitative and qualitative features of 18F-FDG
uptake in sarcoidosis patients with and without cardiac involvement, in addition to patients
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with dilated cardiomyopathy and control subjects with normal hearts. They measured SUV
values in the 17 myocardial segments and calculated the average SUV value and standard
deviation of the SUV value. Then a coefficient of variation (as a metric of image
heterogeneity) was computed as the SD of SUV divided by the average of SUV. The results
of that study demonstrated that 18F-FDG uptake was distinctly heterogeneous in patients
with cardiac sarcoidosis with a higher coefficient of variation of the SUV (0.25±0.05)
compared with control subjects (0.14±0.03, P<0.01) and compared with subjects with non
cardiac sarcoidosis (0.14±0.03, P<0.01) and dilated cardiomyopathy (0.15±0.02, P<0.01),
and therefore diagnostic of the disease.

While 18F-FDG PET has not been included in the most recent update to the Japanese
Ministry guidelines [9••, 10], the existing data to date support the role of 18F-FDG PET as a
sensitive technique for the diagnosis of cardiac sarcoidosis.

Role of 18F-FDG PET in the Management of Patients with Cardiac

Sarcoidosis
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Although not prospectively tested in double-blinded randomized clinical trials, early

administration of corticosteroid therapy in patients with revealed active cardiac sarcoidosis
has been associated with prevention of left ventricular function decline and remodeling [3,
36, 37]. Based on several retrospective small cohort analyses, it is suggested to start oral
prednisone at 30 mg daily [16••] (or 60 mg every other day) for 3 months and eventually
initiate a long tapering process over several months with serial monitoring of disease activity
with imaging and dose adjustments to decide on minimal maintenance dose or complete
withdrawal. As suggested, cardiac imaging plays a relatively important role in this decision
process (Fig. 3), however the evidence supporting this approach is not without controversy.

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In a stratified analysis by Chiu et al. [38] based on baseline left ventricular ejection fraction,
only subjects with an EF of 30 %–55 % had a statistical improvement in ventricular function
compared with patients with an EF <30 %. This finding and others similar contributed to
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suggest that there might be a threshold of left ventricular EF where recovery becomes
unlikely despite immunosuppressive therapy, stressing the importance of early recognition
and management of cardiac sarcoidosis [39, 40••, 42].

The role of 18F-FDG PET imaging in managing patients with cardiac sarcoidosis remains to
be prospectively defined and supported by evidence. However, based on pathophysiologic
and molecular imaging mechanisms, one may surmise scenari where it may be important.
Specifically, to determine not only structural and pathologic changes due to cardiac
sarcoidosis but also to assess disease activity and serial temporal changes potential changes
that may be secondary to therapeutic interventions.

Yamagishi et al. [14] described 7 patients diagnosed with cardiac sarcoidosis based on the
Japanese Ministry Guidelines criteria that were treated with corticosteroids and underwent a
cardiac PET a month later. 18F-FDG uptake was markedly diminished in size and intensity
in 5 patients and disappeared completely in 2 patients. Furthermore, 3 of these patients
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demonstrated improvements and/or disappearance of conduction abnormalities or

ventricular tachycardias. In the study by Tahara et al. [9••], comparing patients with and
without cardiac involvement of sarcoid, in addition to patients with dilated cardiomyopathy
and control subjects with normal hearts, the coefficient of variation of the SUV decreased
significantly in the 9 cardiac sarcoidosis patients treated with steroids (0.24±0.05 to
0.14±0.06, P<0.005) to a level similar to that of dilated cardiomyopathy or healthy controls
suggesting that this measure could be a surrogate of disease activity and potentially aid in
following response to therapy.

A case-report also reported resolution of a complete heart block by ECG after 1 month of
steroid therapy in parallel to disappearance of increased myocardial metabolic activity as
evidence by 18F-FDG uptake on serial PET studies [15]. In another case report, Matthews et
al. [43••] describe a patient presenting with congestive heart failure, biopsy-proven
sarcoidosis, and imaging findings consistent with cardiac involvement as evidenced with
extensive 18F-FDG uptake in both the left and right ventricles as well as multiple focal areas
of myocardial hyperintense signals on T2-weighted MRI images and corresponding areas of
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late gadolinium enhancement. The authors go on to describe significant clinical

improvement after initiation of optimal medical heart failure therapy and corticosteroids.
Subsequent follow-up CMR imaging at 3- and 9 months demonstrated improvements in left
ventricular EF as well as near disappearance of the abnormal T2 signals but persistent late
gadolinium enhancement. However, the 3- and 12-month 18F-FDG PET demonstrated
complete resolution of any cardiac, or extracardiac sarcoid activity, illustrating that while
CMR and 18F-FDG PET were both helpful in establishing the diagnosis of cardiac sarcoid
involvement, only 18F-FDG PET imaging serial imaging demonstrated serial findings
mirroring disease activity correlating with potential response to therapy.

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Role of 18F-FDG PET in Assessing Prognosis

Several studies have confirmed that cardiac involvement in sarcoidosis portends a poor
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prognosis [44]. Granulomatous infiltration can lead to progressively worsening heart failure
[23] and life-threatening cardiac arrhythmias [23]. Sudden death was shown to be the most
frequent cause of death among patients with cardiac sarcoidosis [11].

In an attempt at investigating whether subtle cardiac involvement on sensitive radiographic

imaging modalities predicts severity of cardiac dysfunction and worse prognosis, Betensky
et al. [45] retrospectively studied 45 patients with implantable cardiac defibrillators (ICDs)
and biopsy-proven or highly suspected cardiac sarcoidosis based on advanced cardiac
imaging. Twenty-six patients (58 %) had findings consistent with cardiac sarcoidosis
on 18F-FDG PET imaging. These authors found that ventricular tachycardia (VT) and/or
ventricular fibrillation (VF) requiring ICD therapies was common and significantly
associated with longer device follow-up time, depressed left ventricular systolic function,
and the presence of complete heart block. Interestingly, 4 of the 7 patients with preserved
left ventricular EF and appropriate ICD therapy had positive PET scans (as opposed to
positive CMR only), and the authors suggested that active myocardial inflammation may be
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a potential marker for VT risk in this subgroup. Furthermore, 11 of the 26 patients (42.3 %)
with positive 18F-FDG scans had VT/VF as opposed to 2 of the 7 patients (28.6 %) with
negative 18F-FDG scans and positive CMR or biopsy only. The authors concluded that in
the setting of a positive 18F-FDG scan, an EF ≥ 35 % did not appear to be entirely protective
with regard to arrhythmias.

Isiguzo et al. [25] conducted a retrospective chart review of 18 patients in order to ascertain
the utility of 82Rb/18F-FDG PET scan for assessment of disease activity in patients with
cardiac sarcoidosis. The positive predictive value of 82Rb and 18F-FDG PET scan showing
over 6 % perfusion-metabolism mismatch for detecting clinically active cardiac sarcoidosis
was 100 %. However, the test had lower specificity (62.5 %).The authors concluded that the
finding of a greater than 6 % mismatch is highly indicative of clinically active disease, but
more studies are required to predict prognosis.

Mehta et al. [23] prospectively evaluated 62 patients with biopsy-proven extracardiac

sarcoidosis but with preserved left ventricular EF and without clinical evidence of cardiac
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involvement. Twenty-five of them were screened by 18F-FDG PET for cardiac involvement,
and 22 of these patients (88 %) were found to have abnormalities and were referred for
electrophysiologic programmed electrical stimulation (EPS) in order to determine their risk
of sustained ventricular arrhythmias and sudden cardiac death. Over a mean follow-up of 1.8
years, no patient died or had ventricular arrhythmias, and the authors concluded that sarcoid
lesions seen on 18F-FDG scans do not predict arrhythmias in patients with preserved cardiac
function. However, it should be noted that the cohort studied excluded patients with pre-
existing heart disease, which is a known predictor of survival in cardiac sarcoidosis [39].
Furthermore, several patients were on therapy with systemic corticosteroids, which may
favorably modify the myocardial substrate.

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In the largest study to date, Blankstein et al. [34] studied 125 patients who underwent
myocardial perfusion imaging and 18F-FDG PET imaging following a low carbohydrate-
high fat diet. These patients were followed up for 1.6 years for major cardiac events (n=38)
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of ventricular tachycardia (n=33) or death (n=10). Subjects in this study were grouped
according to perfusion/18F-FDG uptake: normal perfusion/normal 18F-FDG; either abnormal
perfusion or abnormal 18F-FDG; or both abnormal perfusion and abnormal 18F-FDG. The
authors showed that the presence of both a perfusion defect and abnormal 18F-FDG is
associated with an increased risk of major cardiac events (hazard ratio of 2.8, P<.01) after
adjusting for EF.

Further prospective studies with larger patient cohorts are needed to elucidate the diagnostic
and prognostic relevance of 18F-FDG PET in the management of cardiac sarcoidosis.

Challenges with 18F-FDG Imaging for Myocardial Sarcoidosis

18F-FDG imaging is a sensitive test for the diagnosis of cardiac sarcoidosis. However, it is
not widely available and is expensive. Techniques to suppress myocardial glucose utilization
are not perfect. Patient instructions are crucial to ensure they follow the appropriate diet and
despite dietary compliance, inadequate suppression of 18F-FDG uptake may be seen
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reducing test specificity [35]. Also, although 18F-FDG imaging has been used to assess
response to therapy, the metabolic alterations related to prolonged corticosteroid therapy
make it challenging to perform and interpret 18F-FDG images in these patients. Elevations in
serum glucose and insulin levels due to steroids use may adversely affect 18F-FDG uptake
by normal myocytes and reduce test specificity. Another challenge is the interpretation of
decreased 18F-FDG uptake on the follow-up scan. Firstly, it may be hard to visualize a
change on relative perfusion images (since the image normalizes to any 18F-FDG uptake).
Hence, SUV values and comparison with reference organ uptakes are critical for appropriate
interpretation of these images. Also, a reduction in myocardial 18F-FDG uptake could mean
resolution of inflammation (normal myocytes) or progression of disease process and
fibrosis. Perfusion imaging is therefore critical even on the follow-up scans to distinguish
these 2 entities (see Fig. 2, panels normal and fibrosis), as perfusion should be normalized in
the former and should be worse in the latter scenario.

Role of 18F-FDG PET in Assessing Cardiac Sarcoidosis in the era of

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Multimodality Cardiovascular Imaging

Several techniques can be used to image cardiac sarcoidosis. Echocardiography is easy to
obtain and important for determination of left ventricular systolic function. Small focal wall
motion abnormalities [46] or aneurysms in a non-coronary distribution and elevated
pulmonary artery systolic pressure can be clues to sarcoid cardiac involvement. However, it
is not easy to distinguish wall motion abnormalities related to cardiac sarcoidosis from
coronary artery disease or other etiologies. Likewise, perfusion defects on myocardial
perfusion imaging can be nonspecific. Also, perfusion imaging and 67Gallium imaging are
relatively insensitive compared with 18F-FDG PET and gadolinium enhanced delayed CMR.
Presently, 18F-FDG PET and gadolinium enhanced delayed CMR remain the main stays for
the diagnosis of cardiac sarcoidosis.

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Accumulating data support the role of 18F-FDG PET as an accurate technique likely to aid
in the diagnosis of cardiac sarcoidosis. 18F-FDG PET has the advantage of high diagnostic
accuracy and has been shown to be equally or more sensitive than delayed enhancement
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CMR in detecting myocardial lesions from cardiac sarcoidosis. Furthermore, 18F-FDG PET
has several practical advantages over CMR as it and can be utilized in patients in whom
CMR is contraindicated, as in patients with impaired renal function and/or those with
implanted metallic devices. The percentage of patients with indwelling cardiac devices is not
negligible in this population, as many patients with cardiac sarcoidosis may present with
heart block requiring pacemaker or recurrent ventricular arrhythmias and ICD implants. 18F-
FDG PET also offers assessment of disease activity based on SUV values as well as
assessment of perfusion patterns, whereas CMR is somewhat limited in this capability
[43••]. Furthermore, the acquisition of whole-body 18F-FDG PET/CT images has the
advantage of evaluating the extent of systemic disease beyond the myocardium. Therefore,
inclusion of 18F-FDG PET in current guidelines as an alternative to other nuclear techniques
or as a stand-alone investigation may be a consideration [5•].

Taken together, for a definitive diagnosis and management all patients will likely benefit
from an echocardiogram and either cardiac MRI or 18F-FDG PET. One could utilize CMR
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as an initial test in patients with suspected cardiac sarcoidosis. Gadolinium enhanced CMR
with delayed imaging offers the advantage of high sensitivity and spatial resolution, in
addition to no radiation exposure. If negative, 18F-FDG PET can be avoided. If gadolinium
enhancement is seen on CMR and cardiac sarcoidosis is thought to be plausible in the
adequate clinical context, 18F-FDG PET imaging could be performed to establish baseline
disease activity, assess need for initiation of medical therapy and monitor response to
treatment over time. Alternatively, in patients with contraindication to performing
CMR, 18F-FDG PET could be used as first line imaging.

Conclusion
The diagnosis of cardiac sarcoidosis remains elusive and subject to various approaches.
Early diagnosis is particularly important given that steroid therapy in patients with
established cardiac sarcoid and active inflammation should be initiated before left
ventricular systolic function declines [38]. Endomyocardial biopsy can be of limited
diagnostic yield; in addition to being invasive and posing an associated risk of morbidity, it
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may lack sensitivity because myocardial involvement is patchy and not homogenous [47].
The life-threatening complications of cardiac sarcoidosis, coupled with the potential benefit
of early treatment, have made the utilization of more sensitive imaging modalities crucial in
an attempt for early diagnosis and management.

While the revised Japanese Ministry Guidelines published in 2006 are currently the official
diagnostic guide and provide an excellent framework to identify patients with cardiac
involvement, they utilize techniques that lack sensitivity and specificity. Imaging modalities
that can both identify disease activity and potentially predict response to therapy are needed
to improve management of this disease. In the last decade alone, 18F-FDG PET has
substantially enhanced detection of cardiac sarcoid, and is proving to be a very useful
imaging technique in diagnosis, assessing disease activity, monitoring treatment response

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and risk assessment in patients with sarcoidosis. As data about 8F-FDG PET continues to
emerge, there will be a need for standardization of the imaging technique and revision of the
diagnostic criteria.
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Acknowledgments
Sharmila Dorbala has received salary support from a research grant from the National Institutes of Health
(5K23HL092299-03); has received grant support from Astellas Global Pharma Development, Bracco Diagnostics;
has received travel/accommodations expenses covered or reimbursed from RSNA, ASNC.

References
Papers of particular interest, published recently, have been highlighted as:

• Of importance

•• Of major importance

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ImagingGuidelinesPETJuly2009.pdf.
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tomography enhances prognostic assessments of patients with suspected cardiac sarcoid. J Am
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of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J
Cardiol. 2001; 88:1006–10. [PubMed: 11703997]
40 ••. Mantini N, Williams B Jr, Stewart J, Rubinsztain L, Kacharava A. Cardiac sarcoid: a clinician’s
review on how to approach the patient with cardiac sarcoid. Clin Cardiol. 2012; 35:410–5.
[PubMed: 22499155] Recent review paper summarizing several current concepts in the diagnosis
and managements of patients with cardiac sarcoidosis.
41. Ohira H, Tsujino I, Ishimaru S, Oyama N, Takei T, Tsukamoto E, 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; 35:933–41. [PubMed: 18084757]
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97:173–82. [PubMed: 15458680]
43 ••. Matthews R, Bench T, Meng H, Franceschi D, Relan N, Brown DL. Diagnosis and monitoring
of cardiac sarcoidosis with delayed-enhanced MRI and 18F-FDG PET-CT. J Nucl Cardiol. 2012;
19:807–10. [PubMed: 22466988] Interesting case-report illustrating the differential information
provided by 18F-FDG PET and cardiac MRI.
44. Yazaki Y, Isobe M, Hayasaka M, Tanaka M, Fujii T, Sekiguchi M. Cardiac sarcoidosis mimicking
hypertrophic cardiomyopathy: clinical utility of radionuclide imaging for differential diagnosis.
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45. Betensky BP, Tschabrunn CM, Zado ES, Goldberg LR, Marchlinski FE, Garcia FC, et al. Long-
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term follow-up of patients with cardiac sarcoidosis and implantable cardioverter-defibrillators.

Hear Rhythm. 2012; 9:884–91.
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Med. 2002; 23:513–27. [PubMed: 16088647]
48 ••. Ohira H, Tsujino I, Yoshinaga K. (1)F-Fluoro-2-deoxyglucose positron emission tomography in
cardiac sarcoidosis. Eur J Nucl Med Mol Imaging. 2011; 38:1773–83. [PubMed: 21559980] This
reference provides an excellent overview for imaging techniques and patient preparation.

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Fig. 1.
Perfusion and 18F-FDG PET imaging protocol. All patients are instructed to take a high-fat low-carbohydrate diet the day prior
with or without additional overnight fast. A rest myocardial perfusion imaging study is first performed followed by injection
of 18F-FDG. Some sites use IV (intravenous) unfractionated heparin (50 units/kg) about 15 minutes prior to the IV injection of
10–12 mCi of 18F-FDG. After a 90-minute uptake period, cardiac and partial whole body PET images (cerebellum to mid-thigh)
are acquired
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Fig. 2.
Perfusion and metabolism patterns in various stages of cardiac sarcoidosis. This figure demonstrates perfusion/metabolism
patterns as described in the table
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Fig. 3.
PET perfusion and 18F-FDG imaging at baseline and after 6 months of high-dose steroid therapy. These images were obtained in
a 51-year-old man being evaluated for heart block and dizziness. A cardiac MRI was suggestive of cardiac sarcoidosis. Invasive
coronary angiogram revealed normal epicardial coronary arteries. a, Baseline 82rubidium perfusion and 18F-FDG images in
color in alternate rows displayed as short axis, horizontal long axis, and vertical long axis images along with partial whole body
FDG images in grey scale in the coronal, sagittal, and transaxial projections. On the baseline images, there are small and mild,
patchy perfusion defects in the basal and mid anteroseptal and inferoseptal walls with a corresponding mismatch on the FDG
images. Increased 18F-FDG uptake is also noted in the right ventricular free wall. Regions of the myocardium with normal
perfusion (lateral and inferior walls) show no 18F-FDG uptake consistent with excellent suppression of myocardial glucose
utilization by the normal myocardium. The partial whole body images in grey scale show increased 18F-FDG uptake in the
bilateral upper para-tracheal, anterior mediastinal, right lower para-tracheal, subcarinal, para-esophageal, and bilateral hilar
lymph nodes. b, Post-treatment (6 months after high dose steroid therapy) 82rubidium perfusion and 18F-FDG images in color

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along with partial whole body FDG images in grey scale as described previously. The small and patchy perfusion defects in the
anterior wall and the inferoseptal wall are improved. There was no myocardial 18F-FDG uptake (only blood pool activity)
consistent with excellent suppression of myocardial glucose utilization by the normal myocardium along with no 18F-FDG
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uptake in the regions with previously increased 18F-FDG uptake, suggesting interval improvement with high dose steroid
therapy. Improvement/near complete resolution of 18F-FDG uptake is noted in the heart and lymph nodes on the partial whole
body images. The post- treatment images show more pronounced foci of splenic 1F-FDG uptake compared with baseline
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Table 1

Japanese Ministry Guidelines for diagnosis of cardiac sarcoidosis [9••, 10]

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Histologic diagnosis group

Cardiac sarcoidosis is confirmed when endomyocardial biopsy specimens demonstrate noncaseating epithelioid cell granulomas
with histological or clinical diagnosis of extracardiac sarcoidosis.
Clinical diagnosis group
Although endomyocardial biopsy specimens do not demonstrate noncaseating epithelioid cell granulomas, extracardiac sarcoidosis
is diagnosed histologically or clinically and satisfies the following conditions and more than 1 in 6 basic diagnostic criteria.
A. 2 or more of the 4 major criteria are satisfied.
B. 1 in 4 of the major criteria and 2 or more of the 5 minor criteria are satisfied.

Major criteria Minor criteria

1 Advanced atrioventricular block. 1 Abnormal ECG findings: ventricular arrhythmias (ventricular
tachycardia, multifocal or frequent PVCs), CRBBB, axis
2 Basal thinning of the interventricular septum. deviation or abnormal Q-wave.
3 Positive 67gallium uptake in the heart. 2 Abnormal echocardiography: regional abnormal wall motion or
morphological abnormality (ventricular aneurysm, wall
4 Depressed ejection fraction of the left ventricle (<50 thickening).
%).
3 Nuclear medicine: perfusion defect detected by 201thallium
or 99mtechnetium myocardial scintigraphy.
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4 Gadolinium-enhanced CMR imaging: delayed enhancement of

myocardium.
5 Endomyocardial biopsy: interstitial fibrosis or monocyte
infiltration over moderate grade.
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Table 2

Sensitivity and specificity of 18F-FDG PET for the diagnosis of cardiac sarcoidosis
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Study Year Number of patients Cohort Diagnosis Sensitivity (%) Specificity (%)
Yamagishi 2003 17 Cardiac sarcoid histologic 100 n/a
Okumura 2004 22 Sarcoid histologic 100 91
Ishimaru 2005 32 Sarcoid clinical 100 82
ECG and Holter
Ohira 2008 21 Suspected cardiac sarcoid 88 39
diagnosis
Langah 2009 65 Suspected cardiac sarcoid suspected sarcoid 85 90
Weighted Mean 168 89.9 81.4
Mean 168 91 75.5

All studies with 18 F-FDG PET against gold standard of Japanese Ministry Guidelines. (Adapted with permission from: Ohira H, Tsujino I,
Yoshinaga K. (1) F-Fluoro-2-deoxyglucose positron emission tomography in cardiac sarcoidosis. Eur J Nucl Med Mol Imaging. 2011;38:1773–83
[48••]
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