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► Additional supplemental
material is published online
only. To view, please visit the
journal online (http://d​ x.​doi.​
org/1​ 0.​1136/​heartjnl-​2022-​
321379).
1
Department of Internal
Medicine, College of Medicine,
Seoul National University, Seoul,
South Korea
2
Seoul One-­Heart CV Clinic,
Seoul, South Korea
Correspondence to
Emeritus Prof. Dae-­Won Sohn,
Seoul National University
College of Medicine Department
of Internal Medicine, Seoul
03080, Korea (the Republic of);
​dwsohn@​snu.a​ c.​kr
Received 21 September 2022
Accepted 20 December 2022
© Author(s) (or their
employer(s)) 2023. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Sohn D-­W, Park J-­
B. Heart Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
heartjnl-2022-321379
Cardiac sarcoidosis
Dae-­Won Sohn  ‍ ‍,1,2 Jun-­Bean Park1
ABSTRACT
The diagnostic yield of endomyocardial biopsy in cardiac
sarcoidosis (CS) is quite low because of the patchy
involvement, and for the diagnosis of CS, existing
guidelines required histological confirmation. Therefore,
especially for isolated CS, diagnosis consistent with the
guidelines cannot be made in a large number of patients.
With recent developments in imaging modalities such as
cardiac magnetic resonance and 18-­fluorodeoxyglucose
positron emission tomography, diagnosing CS has become
easier and diagnostic criteria for CS not compulsorily
requiring histological confirmation have been suggested.
Despite significant advances in diagnostic tools, large-­scale
studies that can guide treatment plans are still lacking,
and treatment has relied on the experience accumulated
over the past years and the consensus of experts. However,
opinions vary, depending on the situation, which is quite
puzzling for the physician treating CS. Moreover, with
the advent of new immunosuppressant agents, these
new drugs have been applied under the assumption
that the effect of immunosuppression is not much
different from that of other well-­known autoimmune
diseases that require immunosuppression. However, we
should wait to see the beneficial effects of these new
immunosuppressants before we attempt to apply these
agents in our clinical practice. This review summarises
the widely used diagnostic criteria, current diagnostic
modalities and recommended treatments for sarcoidosis.
We have added our opinions on selecting or modifying
diagnostic and treatment plans from the diverse current
recommendations.
INTRODUCTION
Sarcoidosis is a granulomatous disease of unknown
aetiology characterised by multisystem involve-
ment. Among the organs involved in systemic
sarcoidosis, the lung is by far the most frequently
involved (>90%), and cardiac involvement is noted
only in 2%–3% of the patients.1 2 While this low
incidence of cardiac sarcoidosis (CS) reflects the
low incidence of cardiac involvement in systemic
sarcoidosis, a lack of eagerness to diagnose CS may
also play a role.
Previously, myocardial thickness and motion
assessed by echocardiography were the only param-
eters available for the detection of myocardial injury
associated with inflammation. With the evolution of
imaging modalities, such as cardiac magnetic reso-
nance (CMR) and 18-­fluorodeoxyglucose–positron
emission tomography (FDG-­ PET), information
about myocardial injury or inflammation may be
obtained in the early phase of CS.
From a therapeutic perspective, many new immu-
nosuppressants have been introduced. Moreover,
the roles of current interventional therapies, such as
ablation therapy for tachyarrhythmia and implant-
able cardioverter defibrillator (ICD) implantation,
remain to be defined.
Sohn D-­W, Park J-­B. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321379
EPIDEMIOLOGY
Although infrequently affected, the heart is an
important site of involvement, and a major deter-
minant of prognosis. The first case of heart
involvement in sarcoidosis was reported by Bern-
stein in 1929, and clinically apparent CS has been
noted in approximately 5%–10% of patients with
systemic sarcoidosis.1 3 However, a much higher
rate of myocardial involvement of approximately
20%–30%4 to over 70%5 has been reported in
autopsy series. With the development of imaging
modalities and clinical awareness of CS, the inci-
dence of the diagnosis of cardiac involvement in
systemic sarcoidosis may reach that of autopsy
series.
PATHOGENESIS
Sarcoidosis is a multisystem granulomatous disease
characterised by the presence of non-­ caseating
granulomas in the involved organ.6 7 In granuloma-
tous disease, granuloma formation is thought to be
a host defensive mechanism to prevent the spread
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of pathogens or irritant events.8
Pathological processes are believed to start with
circulating monocytes that interact with a specific
antigen and differentiate into specific antigen-­
presenting cells (APCs). In this process, in the pres-
ence of cytokines, APC promotes CD4+ T cells
expressing T-­ helper (Th)-­ 1, Th-­ 17 and Th-­ 17.1
cells. By secreting their specific cytokines, corre-
sponding responses are elicited and inflammation
in the affected sites is promoted (figure 1). Gener-
ally, a regulatory T (Treg)-­cell response is known to
repress local helper T-­cell responses and has anti-­
inflammatory action. In sarcoidosis, although not
always pronounced, extensive local inflammation is
associated with peripheral anergy, which is called
the ‘immune paradox’. Several studies have shown
that Treg cells are amplified at the lesion site and as
well as in the peripheral blood but are still unable
to control local inflammation as tumour necrosis
factor (TNF)-α is weakly inhibited but plays a role
in granuloma formation at the lesion site.9
This simple description of immunopathogenesis
is to help understand our therapeutic strategy. The
important role of Th-­17 cells in the pathogenesis,
and CD+ T-­cell plasticity were only recently appre-
ciated. Much is still unknown about the role of Treg
and serum amyloid A protein in sarcoidosis.
Considering the role of APC in initiating this
process, it is natural to consider the role of major
histocompatibility complex (MHC) class II mole-
cules, normally found only on APC. In humans,
the MHC class II protein complex is encoded by
the human leucocyte antigen (HLA) gene complex,
and an association between genetic susceptibility
and HLADQ− and DR− genes has been reported.
Associations between non-­HLA genes, such as the
  1
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Heart: first published as 10.1136/heartjnl-2022-321379 on 11 January 2023. Downloaded from http://heart.bmj.com/ on February 14, 2023 at Keimyung University Dongsan Medical Center.
Figure 1  Immunopathogenesis and treatment targets. On antigen presentation to a TCR on a T lymphocyte via MHC class II molecules, various
cytokines, chemokines and other soluble mediators are produced, and polarisation of T cell into Th1, Th17 and Th17.1 cells is promoted. Th1, Th17 and
Th17.1 responses in affected sites together with the impaired Treg cell response allows enhanced local effector T-­cell responses to persist, resulting in

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chronic sarcoidosis. APC, antigen-­presenting cell; MHC, major histocompatibility complex; TCR, T-­cell receptor; Th, T helper; Treg, regulatory T.

butyrophilin like 2 (BTNL2) gene, located close to the MHC II
region, and predisposition or susceptibility to sarcoidosis have
also been reported.
In the therapeutic concept, many different kinds of cytokines
are involved in the pathological process, and second-­line or third-­
line drugs have different targets10 in their anti-­ inflammatory
actions (figure 1).
DIAGNOSIS
Diagnostic criteria
Two major diagnostic criteria for CS have been widely cited and
applied in clinical practice. The first is the criteria originally
suggested by the Japanese Ministry of Health and Welfare11 in
1993 and later revised by Japanese organisations in 2006, 2014
and 201512–14 (online supplemental table 1). The second is the
criteria included in the consensus statement from the Heart
Rhythm Society (HRS)15 in 2014 (online supplemental table 2).
According to these criteria, when sarcoidosis is not histologically
confirmed in the heart, the presence of extra-­CS should be docu-
mented for the diagnosis of CS.
Due to the patchy nature of involvement in CS, the diagnostic
yield of endomyocardial biopsy (EMB) has been reported to be
approximately 20%.16 17 Even with electrogram-­guided EMB,18
non-­ caseating granuloma was noted in 5/13 specimens from
three patients who were finally diagnosed as CS.
Because of the difficulty in the histological confirmation of
non-­caseating granulomas in the heart, even with compelling clin-
ical evidence of CS, the diagnosis of extra-­CS has become a top
priority. However, there are cases of isolated CS19 20 in which the
diagnosis of extra-­CS cannot be made. Although it is debatable
whether isolated CS represents isolated involvement of the heart
for the entire course of the disease,21 the existence of isolated
CS, at least at a certain time point in the course of disease, is
2 Sohn D-­W, Park J-­B. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321379
not in question. In 2016, the Japanese Circulation Society (JCS)
updated the guidelines for diagnosing and treating CS.14 This
guideline includes diagnostic criteria for isolated CS (table 1A).
In essence, isolated CS can be diagnosed without demonstrating
extra-­CS and in the absence of histological confirmation in biop-
sies from the heart, when one absolute criterion of radionuclide
imaging and an additional three other major criteria in their
previous criteria are satisfied. However, considering that FDG-­
PET can show positive results in non-­inflammatory conditions
as well as in situations when myocardial FDG uptake is inad-
equately suppressed, FDG-­PET as an absolute criterion might
lower the sensitivity or specificity of the criteria. We previously
proposed a scoring system for CS (table 1B).22 Compared to the
2016 JCS criteria for isolated CS, our scoring system simply gave
more weight to FDG-­PET findings instead of regarding FDG-­
PET findings as an absolute criterion, excluded the left ventric-
ular (LV) dysfunction not associated with regional wall motion
abnormality (RWMA) unusual for the coronary artery territory
and atrioventricular (AV) conduction disturbance, and included
the possible accompanying clinical findings.
Electrocardiogram and Holter monitoring
Two clinically important findings focused on by many clinicians
are:(1) conduction disturbance and (2) ventricular tachycardia
(VT). As the predilection site of CS is the basal anterior septum,
the infra-­His block is more likely to be expected in cases of
complete AV block (figure 2). Therefore, in treating premature
ventricular or atrial contraction, which are frequently encoun-
tered in patients with sarcoidosis, beta blockers should be care-
fully reconsidered in patients with first-­degree AV block as it can
represent trifascicular block.
In patients with CS, epsilon waves are reported and do not
necessarily indicate the diagnosis of arrhythmogenic right
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Heart: first published as 10.1136/heartjnl-2022-321379 on 11 January 2023. Downloaded from http://heart.bmj.com/ on February 14, 2023 at Keimyung University Dongsan Medical Center.
Table 1  JCS revised diagnostic guideline for isolated CS and SNUH
proposed criteria for CS: diagnosis without histological confirmation
(A) JCS revised diagnostic guideline for isolated CS*
Prerequisite
► No clinical findings characteristic of sarcoidosis are observed in any organs other
than the heart (patient should be examined in detail for respiratory, ophthalmic
and skin involvements of sarcoidosis. When the patient is symptomatic, other
aetiologies that can affect the corresponding organs must be ruled out).
► 67Ga scintigraphy or 18F-­FDG PET reveals no abnormal tracer accumulation in
any organs other than the heart.
► A chest CT scan reveals no shadow along the lymphatic tracts in the lungs or no Figure 2  (A) Resting EKG shows first-­degree AV block with wide QRS
hilar and mediastinal lymphadenopathy (minor axis >10 mm). complex. As a cause of PR prolongation, the possibility of trifascicular
Major criteria
block should be considered. (B) Intermittent complete AV block noticed
► Advanced atrioventricular block or sustained ventricular tachycardia. during Holter monitoring shows wide QRS escape beats suggesting
► Basal thinning of the interventricular septum or morphological abnormality infra-­His block. (C) Even if only high echogenicity is noted at the basal
(aneurysm, wall thinning or wall thickening). anteroseptal segment, certain pathology is likely to be present in the
► Depressed ejection fraction (<50%) or RWMA. presence of infra-­His AV block (online supplemental video) (D) Therefore,
► Abnormal uptake of 67Ga or 18F-­fluorodeoxyglucose in the heart. the tiny mid-­wall delayed enhancement at the basal anterior septum
► Delayed gadolinium enhancement on CMR.
(circle), which can be ignored in other cases, is an important finding in
(B) SNUH proposed criteria for CS this case. AV, atrioventricular.
Findings Score†
► Echocardiographic finding: RWMA unusual for coronary artery territory 1 this finding is considered in echocardiographic diagnosis, many
or mimicking ARVD coronary artery territory. patients will be missed, as the reported incidence of this finding
► CMR: multiple patch mid-­wall or subepicardial delayed enhancement. 1 is only 20%.
► FDG-­PET: single focal. 1 Cyclic variation of integrated backscatter or longitudinal
► FDG-­PET: multiple patch. 2 strain to increase the sensitivity CS detection was suggested.
► Endomyocardial biopsy: focal fibrosis or collection of histiocyte. 1 However, considering the limited additive effect of these modal-
► Finding suggesting systemic involvement but not amendable to biopsy. 1 ities in increasing sensitivity or specificity, it would be better to

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Prerequisition
resort to other imaging modalities such as CMR or FDG-­PET
► Not associated with known genetic mutation in ARVD, in patient with in patients with suspected CS showing subtle echocardiographic
echocardiographic features mimicking ARVD. abnormalities.
► Not a carrier state of hereditary myopathy, for example, Duchenne’s or Becker’s In addition to the role of echocardiography in diagnosing CS,
muscular dystrophy. echocardiography is an essential tool in monitoring LV function
Systemic involvement that is not amendable to biopsy in patients with CS.
► Uveitis or its possible sequelae. Several studies24 25 have reported diagnostic ambiguities
► Raynaud’s syndrome.
between CS and ARVD. Therefore, in cases where echocardi-
► Interstitial lung disease.
► Neurological sings with possible CNS involvement. ography is suggestive of ARVD, the possibility of CS should be
*Isolated CS is diagnosed clinically when the fourth criterion and at least three
considered, and histological or genetic evidence should be sought
other criteria of major criteria are satisfied.
†Cardiac sarcoidosis can be diagnosed when the score is 4 or higher.
ARVD, arrhythmogenic right ventricular dysplasia; CMR, cardiac magnetic
resonance; CNS, central nervous system; CS, cardiac sarcoidosis; FDG-­PET, 18-­fluoro-­
2-­deoxyglucose–positron emission tomography; RWMA, regional wall motion
abnormality; SNUH, Seoul National University Hospital.

ventricular dysplasia (ARVD).23 However, this phenomenon

should be interpreted considering that differentiating between
CS and ARVD is difficult. Holter monitoring is frequently
performed to detect the presence of VT even in patients without
symptoms of palpitation.

Echocardiogram
The typical echocardiographic finding is multiple regional wall
motion abnormalities (RWMA) that do not match the coronary
artery territory. Multiple patchy sarcoid involvement does not
always result in multiple RWMA. Moreover, RWMA unusual for
coronary artery territory is difficult to determine, even for an
expert echocardiographer. CT coronary angiography is helpful
in this situation, that is, RWMA in patients with normal coro-
nary arteries. Figure 3  Involvement of basal anteroseptal segment, which is a
Among RWMA, thinning of the basal anterior septum seems relatively unique feature of cardiac sarcoidosis. (A) Fibrosis without wall
to be rather specific to CS, although the exact specificity of this thinning, (B) endocardial fibrosis with wall tinning, (C) diffuse septal
finding has not been elucidated (figure 3). However, if only thinning and (D) localised septal thinning.
Sohn D-W
­ , Park J-­B. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321379 3
 Review
Figure 4  (A,B) Difference in echocardiographic features 16 months
apart. In addition to the slightly enlarged right ventricle, the RV apex
showed aneurysmal bulging during systole (arrowheads), mimicking
ARVD. (C,D) Explanted heart after cardiac transplantation. The
myocardium stained blue (Masson trichrome stain), suggesting focal
fibrosis. In addition, large areas of fatty tissue replacement are seen
in the right and left ventricles. ARVD, arrhythmogenic right ventricular
dysplasia; RV, right ventricular.
for differential diagnosis. In one patient with CS who under-
went cardiac transplantation, serial echocardiography showed
that the right ventricular (RV) morphology became similar to
that of ARVD over time, and histological examination of the
explanted heart showed replacement by fatty tissue instead of
fibrosis (figure 4).
CT coronary angiogram
Because of the presence of RWMA, coronary angiography is not
infrequently performed in patients with CS. Only to confirm
the RWMA which is unusual for the coronary artery territory,
CT coronary angiography is sufficient to achieve the goal. In
addition, on the CT coronary angiogram, we can confirm the
presence of LN’s that are accessible to endobronchial ultrasound
(EBUS)-­guided biopsy. Therefore, the lower para-­tracheal LN
should be covered in CT coronary angiography (figure 5A).
Cardiac magnetic resonance
Based on the pattern of delayed enhancement (DE) on CMR,
differentiation between ischaemic and non-­ ischaemic cardio-
myopathies can be made quite easily26 (figure 5B). A variety
of lesions can be classified as non-­ischaemic cardiomyopathy.
However, if the non-­ischaemic pattern of DE is multiple and
patchy in nature, we cannot think of any disease other than CS.
Moreover, it is not unusual to observe DE in segments without
an RWMA. Therefore, DE evaluation seems more sensitive than
the other methods used in the past to detect cardiac involvement
in sarcoidosis.
Applications of various techniques in CMR have been studied
in CS, such as T2-­weighted images or T1 mapping. However,
despite the large number of publications suggesting the useful-
ness of these techniques, whether these techniques significantly
upgrade the usefulness of CMR in real-­world practice remains
unclear.
In addition to its diagnostic utility, RV involvement can be
assessed in CMR.27 It is reasonable to think that RV involvement
4 Sohn D-­W, Park J-­B. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321379
Heart: first published as 10.1136/heartjnl-2022-321379 on 11 January 2023. Downloaded from http://heart.bmj.com/ on February 14, 2023 at Keimyung University Dongsan Medical Center.
Figure 5  (A) CT coronary angiogram can demonstrate normal
coronary arteries in patients with RWMA, therefore suggesting the
non-­ischaemic nature of RWMA. In addition, the presence of hilar
LNs accessible to EBUS biopsy (arrows) can be assessed. Therefore, CT
coronary angiogram has dual objective. (B) Cardiac magnetic resonance
shows subepicardial DE at the anterior segment (arrowheads) and mid-­
wall DE at inferoseptal and inferior segments (arrows). Subepicardial or
mid-­wall DE indicates non-­ischaemic cardiomyopathy. LAD, left anterior
descending artery; LCx, left circumflex artery; RCA, right coronary artery;
DE, delayed enhancement; EBUS, endobronchial ultrasound; RWMA,
regional wall motion abnormality.
can be detected in the early stage by RV DE compared with RV
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dilatation on echocardiography.
The prognostic value of CMR imaging in patients with CS has
also been studied. In addition to LV DE, RV DE in patients with
CS is reported to be associated with a risk of adverse events,
particularly ventricular tachyarrhythmias.28
18-Fluorodeoxyglucose–positron emission tomography
Several studies have shown that FDG-­PET is more sensitive than
thallium or gallium scans for the diagnosis of CS. Therefore,
FDG-­PET has almost completely replaced other agents, espe-
cially as a fusion image with CT (FDG-­PET/CT). In FDG-­PET,
the normal myocardium’s use of glucose as an energy source
should be adequately suppressed. For this purpose, prolonged
fasting, a high-­fat diet before prolonged fasting, and preadminis-
tration of heparin have been used.
As FDG-­PET findings provide not only the location but also
the activity of the disease, we therefore assigned more weight to
the FDG-­PET results in our suggested criteria, and FDG-­PET
findings are regarded as an absolute criterion in the diagnosis of
isolated CS in the JCS updated guidelines. In addition to its role
in diagnosis, FDG-­PET is used to monitor treatment response
(figure 6A).
To overcome the subjectivity in visual estimation, various
methods based on standardised uptake values (SUVs), including
SUVmax, SUVmean, cardiac metabolic activity, cardiac meta-
bolic volume and coefficient of variance, have been proposed.29
Serum markers
Elevated serum ACE activity in sarcoidosis has been well known
and was frequently used for diagnosis. Although the ACE level
in sarcoidosis might be higher than that in normal subjects, the
sensitivity of the ACE level for detecting sarcoidosis precludes it
being used as a diagnostic test.
Troponin has been proposed for monitoring the disease
activity in patients with CS; however, there are still insufficient
data to define the clinical usefulness in CS. The role of other

Figure 6  (A). FDG-­PET in the assessment of treatment response.
FDG-­PET image findings before (left column) and after (right column)
treatment with steroid. (B) A patient presented with cardiac arrest
and in whom ICD was implanted. FDG-­PET immediately after ICD
implantation (above). Refused taking steroid after a couple of days
of treatment complaining of multiple symptoms, and the patient
was not regularly followed up after discharge. FDG-­PET done 2 years
later (below) showed similar uptake in intensity and distribution
compared with the previous study. There was no significant change in
LV function between two examinations. Hot uptake in FDG-­PET image
does not necessarily indicate presence of active inflammation. FDG-­
PET, 18-­fluoro-­2-­deoxyglucose–positron emission tomography; LV, left
ventricular.
biomarkers, including C reactive protein, in sarcoidosis has been
studied; however, their role in CS remains unclear.
TREATMENT
Usefulness of steroid or immunosuppressant treatments for
CS
In a meta-­analysis30 regarding corticosteroid and immunosup-
pressant therapy, we can recognise that data regarding its effect
on mortality were too limited to conclude that steroid therapy
truly reduces mortality rate in CS. Yazaki et al31 showed better
long-­term survival in patients using steroids; however, patients
whose CS was diagnosed at autopsy were selected as a control
group of non-­steroid user. In one recent study, in contrast, the
mortality was lower in patients without immunosuppressive
therapy (1/21, 4.8%) compared with the group with immuno-
suppression (6/70, 8.6%).32
The effect on LV function was not consistent in the meta-­
analysis. In a study by Nagai et al,33 the composite endpoints
of all-­cause death, symptomatic arrhythmias and heart failure
requiring admission were reduced with steroid therapy. However,
no significant differences were found in terms of cardiac death or
symptomatic arrhythmias between steroid users and non-­users,
which seems to indicate that the main effect of steroid therapy
is reducing heart failure requiring admission by preventing the
deterioration of LV function.
A relatively consistent beneficial effect of steroid or immuno-
suppressant therapy is the recovery of AV conduction. In roughly
half of the patients with high-­grade AV block, recovery of AV
conduction is expected.30
The major clinical effect of glucocorticoids is the anti-­
inflammatory activity. However, glucocorticoid therapy is a
reasonable option in situations where fibrotic lesions are the
dominant finding, expecting an antifibrotic effect. Among
diseases treated with steroids, both active inflammation and
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fibrosis are harmful reactions; therefore, the use of steroids is
not contradictory. However, granulomas represent an inflam-
mation confined to the centre, with fibroblast and collagen
encasing and restricting inflammation, thereby protecting the
surrounding tissue. Therefore, the fibrosis-­ preventing effect
of steroids might help prevent progressive fibrosis later in the
course of the disease but might lessen the protective effect of
granulomas. Therefore, it is desirable to search for active inflam-
mation before starting steroid or immunosuppressant therapies.
Hot spots on FDG-­PET have been regarded as evidence of active
inflammation; however, a hot spot in FDG-­PET can be seen in
conditions other than inflammation. Therefore, in our insti-
tution, we start steroid or immunosuppressant therapy when
additional clinical evidence of active inflammation, such as new
RWMA, recently deteriorated LV function or newly appeared
conduction disturbance is also present. In addition, steroid or
immunosuppressant therapy might be limited to patients whose
LV function is relatively preserved (EF >35%), as the expected
effect of these therapies is to preserve LV function, not recover
already deteriorated LV function, and they seem ineffective in
preventing malignant ventricular arrhythmia in patients with
severely depressed LV function.
Initial steroid dose and treatment strategy
In contrast to pulmonary sarcoidosis, high-­dose prednisolone
(1 mg/kg/day) was recommended as the initial dose34 in cardiac
or neurosarcoidosis expecting minimal treatment failure with
steroid therapy. However, there has been no general consensus
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regarding this high initial dose of prednisolone. In one study,31
the overall survival of patients treated with a high initial dose
(>40 mg/day) did not differ from that of patients treated with
a low dose (<30 mg/day). In this study, dose comparison was
performed on only 75 patients, and the survival curves between
the high-­dose and low-­dose groups showed differences in the
early phases (2–4 years), with similar survival rates after 5 years.
Although this study has shortcomings, many patients, especially
female patients, cannot tolerate high doses of steroids for a long
period. Hence, most experts suggest a low initial dose (0.5 mg/
kg/day of prednisolone) of steroids.7
The currently suggested schemes of steroid treatment in CS, in
large part, have their basis on the schemes used in the treatment
of pulmonary sarcoidosis.35 A low initial dose of steroids is main-
tained for 2–3 months, after which the therapeutic response is
evaluated with FDG-­PET. Once there is a therapeutic response,
the dose of the initial steroid therapy is tapered down to the
maintenance dose for 3 months, and the final dose is maintained
for 9–12 months.7 In our institution, we use the same initial dose
of steroid for 1 month, tapering to the maintenance dose during
the next month, and then the maintenance dose for the next 10
months, with a total duration of treatment of 12 months.
As with the use of steroids in other autoimmune diseases, the
side effects of steroids should be carefully monitored. Consid-
ering the risk of steroid-­induced avascular necrosis of the femoral
head, the patient’s age and occupation should also be considered
before starting steroid treatment.
Treatment strategy in patients unresponsive to initial steroid
therapy
Patients who are non-­responsive to initial steroid therapy must be
separated from those who respond to initial steroid therapy but
fail to taper the steroid to the maintenance dose level (<10 mg/
day). If an equivalent dose of more than 10 mg/day of prednis-
olone is required as the maintenance dose, second-­line drugs,
5
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such as methotrexate or azathioprine, as a corticosteroid-­sparing
agent are usually considered. Clinical data regarding initial treat-
ment with second-­line or third-­line drugs in patients who are
intolerant of initial steroid therapy are lacking.
Non-­responsiveness to the initial steroid therapy is usually
assessed using FDG-­ PET. Even with quantitative assessment,
evaluation of steroid response by FDG-­ PET is not always
straightforward. Therefore, simultaneous clinical assessments,
such as improvement in haemodynamic status or conduction
disturbances, should also be considered while evaluating unre-
sponsiveness (figure 6B).
The most commonly recommended third-­line drug is a TNF
inhibitor. TNF is a proinflammatory molecule; therefore, TNF
inhibitors have been used to treat various autoimmune and
inflammatory diseases. However, preclinical and clinical data
have shown that it might show a paradoxical anti-­inflammatory
and immunomodulatory effects.36 Studies examining TNF-α-de-
ficient animals have reported a critical role of TNF-α in regu-
lating and limiting the extent and duration of the inflammatory
response.37 Therefore, the effectiveness of TNF inhibitors in
other autoimmune diseases may not automatically be extended
to the effectiveness of sarcoidosis.
In patients who are unresponsive to initial steroid therapy, we
stop using steroids through tapering. We observe the disease’s
progress over time rather than continuing therapy with third-­
line drugs.
Bradycardia, VT and sudden death
In patients with advanced conduction disturbance, permanent
pacemaker insertion should be considered according to general
guideline indications. Not infrequently, conduction distur-
bance can be recovered with steroid therapy. Still, it is generally
believed that this recovery is transient, and conduction recovery
does not invalidate the indication for pacemaker insertion.
However, transient does not mean days or weeks; therefore, if
the patient’s haemodynamic condition is stable in the presence
of conduction disturbance, pacemaker insertion might be safely
postponed if the conduction disturbance has recovered.
Due to sudden cardiac death (SCD) in CS, inserting ICD
should be considered when permanent pacing is indicated, as
ICD has a pacemaker function. In the 2017 American Heart
Association/American College of Cardiology/HRS guideline,
ICD implantation is recommended in patients with evidence of
extensive myocardial scarring by CMR or PET scan, even with
an LVEF of >35%.38
In one study analysing myocardial inflammatory diseases in
the Finland study group registry,39 the 5-­year incidence of SCD
in patients with AV block with an EF of <30% and VT was 34%.
Even in patients with a lone AV block with normal EF and no
VT, the 5-­year-­incidence of SCD was 9%. Based on this result,
the authors recommended implanting ICD whenever permanent
pacing is indicated. However, it is noteworthy that even though
ICDs were implanted in 75% of the patients in patients with AV
block with EF of <30% and VT, the 5-­year incidence of SCD
was 34%.
ICD does not prevent non-­arrhythmic causes of SCD, such
as pump failure; therefore, if the patient experiences frequent
shocks associated with VT, the adverse effect of ICD on LV func-
tion should also be considered.
VT is usually treated with antiarrhythmic agents. It is diffi-
cult to draw conclusions regarding the effectiveness of steroids
in suppressing VT. In one report,40 corticosteroid therapy did
not reduce the number of PVC or nonsustained VT (NSVT).
6 Sohn D-­W, Park J-­B. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321379
Heart: first published as 10.1136/heartjnl-2022-321379 on 11 January 2023. Downloaded from http://heart.bmj.com/ on February 14, 2023 at Keimyung University Dongsan Medical Center.
However, a significant reduction in PVCs and NSVT was
observed in patients with less advanced LV dysfunction (EF
≥35%). Contrary to the expected positive effect, an increased
ventricular arrhythmia burden with corticosteroid treatment has
also been reported.41 However, the effects of individual immu-
nosuppressive agents, such as third-­line drugs, might not be the
same as the effect of steroids on ventricular arrhythmia.42
Ablation therapy may be an option for patient refractory to
medical therapy. However, despite successive ablation, the recur-
rence rates are reported to be high.43 44 Several electrophysiolog-
ical explanations for this poor outcome have been suggested,45
and obstacles in catheter ablation do not seem to be solved easily.
ICD insertion is one of the most challenging procedures in
CS. Studies on risk stratification in patients with CS have been
carried out using various modalities, such as the presence of DEs
in CMR, perfusion defects and abnormal FDG uptake, induc-
ible sustained VT in programmed electrical stimulation and RV
involvement.46 However, it is still too early to depend solely on
one or more of these modalities for decision making on ICD
implantation; therefore, following HRS guideline15 has been
recommended (online supplemental table 3).
Correction notice  This article has been corrected since it was first published to
correct author name Jun-­Bean Park.
Contributors  DW-­S wrote the manuscript and prepared the illustrations. JB-­P
reviewed the manuscript and supplemented the missed points to be dealt with in the
manuscript.
Funding  The authors have not declared a specific grant for this research from any
Protected by copyright.
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Not applicable.
Ethics approval  Not applicable.
Provenance and peer review  Commissioned; externally peer reviewed.
Supplemental material  This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
ORCID iD
Dae-­Won Sohn http://orcid.org/0000-0002-1092-3285
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