C a rdi a c S a rc o i d o s i s

Manuel L. Ribeiro Neto, MDa,*, Christine L. Jellis, MD, PhDb,

Paul C. Cremer, MDb, Logan J. Harper, MDa, Ziad Taimeh, MDb, Daniel A. Culver, DOa

KEYWORDS
 Cardiac sarcoidosis  Sarcoidosis  Heart  Cardiomyopathies

KEY POINTS
 It is important to distinguish between clinical manifest diseases from clinically silent diseases.
 Advanced cardiac imaging studies are crucial in the diagnostic pathway.
 In suspected isolated cardiac sarcoidosis, it’s key to rule out alternative diagnoses.

INTRODUCTION In that first report, Dr. Mitchell Bernstein, an

Cardiac involvement is a major cause of morbidity
and mortality in patients with sarcoidosis.1,2
Compared with many other manifestations of the
disease, patients with cardiac sarcoidosis (CS)
have lower health-related quality of life, higher
rates of hospitalization, and higher incidence of
disease-related comorbidities such as fatigue.3,4
Life-threatening conditions, such as high-degree
atrioventricular block, heart failure, and ventricular
arrythmias, frequently affect these patients.5 Not
surprisingly, in a large series from Japan including
320 autopsy cases of sarcoidosis, CS was the
most common cause of sarcoidosis-related
death.6
Despite its clinical significance, a paucity of data
leaves patients and clinicians facing many
unknowns. The definition and prevalence of isolated
CS are still debatable.7–10 The suboptimal specificity
of advanced cardiac imaging and sensitivity of
endomyocardial biopsy inserts challenges in the
diagnostic process.11–14 The optimal dose of corti-
costeroids and choice of immunosuppressive
agents are still unclear.15,16 And the overall prog-
nosis and the prognostic abilities of many individual
test results continue to spark controversies.17–19
HISTORY
The first report of CS dates back to 1929, when
Bernstein and colleagues described a case of
instructor in Medicine at Jefferson Medical College
at the time, described a case of a 52 year old white
man who presented with skin lesions (plaques,
papules, and nodules on face and trunk) and short-
ness of breath with bilateral pleural effusions. The
investigation for tuberculosis was negative, which
included injecting the pleural fluid intraperitoneally
into a guinea pig, with no development of tubercu-
losis 3 months later. The biopsy of the cutaneous le-
sions showed epithelioid cells, lymphocytic plasma
cells, and a few giant cells. In the postmortem ex-
amination, similar lesions were found in the epicar-
dium, bronchial mucosa, and ileum.20
The term “Boeck’s sarcoid” was used in refer-
ence to the Norwegian dermatologist Dr. Caesar
Boeck, the first person to describe the histology
of skin lesions from a patient in 1899 with what is
today known as sarcoidosis.21 The patient, a 36
year old man, presented with skin nodules and pap-
ules of varying size on head, trunk, and extremities,
and swollen lymph nodes. The histology of 2 lesions
demonstrated epithelioid connective tissue cells,
with some giant cells. Infectious causes were not
identified. Boeck named the entity as “multiple
benign sarkoid” due to the perceived histologic af-
finity to sarcoma. He stated his case was identical
to the recently described “Mortimer’s malady” by
Dr. Jonathan Hutchinson in 1898. He also stated
that a similar case had been presented at a derma-
tology congress in 1896, carefully noting “but I do
chestmed.theclinics.com

“Boeck’s sarcoid” with epicardial involvement.20 not know by whom”.21

a
Department of Pulmonary Medicine, Cleveland Clinic, 9500 Euclid Avenue / A90, Cleveland, OH 44195, USA;
b
Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
* Corresponding author.
E-mail address: ribeirm@ccf.org

Clin Chest Med - (2023) -–-

https://doi.org/10.1016/j.ccm.2023.08.006
0272-5231/23/Ó 2023 Elsevier Inc. All rights reserved.
2 Ribeiro Neto et al
Since those first cases of sarcoidosis and CS
were described, autopsy studies further advanced
the understanding of the pathophysiology of car-
diac involvement.6,22 In an American series pub-
lished in 1977, Roberts and colleagues22 analyzed
113 autopsy cases of CS. All patients had either
non-necrotizing granulomas in the heart or trans-
mural scar in the absence of significant coronary ar-
tery disease. The most common locations of
granulomatous inflammation were the left ventricu-
lar (LV) free wall (98%), the ventricular septum
(70%, usually the cephalad portion), the right ven-
tricular (RV) wall (47%), the papillary muscles
(41%), and the atrial wall (22%). The correlation be-
tween the histopathology findings and clinical man-
ifestations is shown in Fig. 1. Granulomas were
found in any portion of the heart (pericardium,
myocardium, and endocardium), but the myocar-
dium was by far the most frequently involved.
DEFINITIONS
CS can be classified into clinically manifest and
clinically silent, based on the presence or absence
of symptoms/effects, respectively.23,24 Clinically
manifest disease seems to affect a small propor-
tion of patients with sarcoidosis, with 2 American
studies showing a prevalence of 1% and
2.3%.25,26 In contrast, clinically silent disease af-
fects a higher proportion of patients with sarcoid-
osis. Studies including consecutive patients with
asymptomatic sarcoidosis have shown preva-
lences of abnormal cardiac magnetic resonance
imaging (CMR) ranging from 13% to 55%.27–29
Recognizing these distinct definitions could help
future studies uncover potential distinct progno-
ses and better individualized treatment strategies.
Perhaps more controversial is the definition of
isolated CS.7–10 Proposed definitions vary from
more strict ones requiring endomyocardial biopsy
documenting non-necrotizing granulomas and
whole-body 18F-fluorodeoxyglucose (FDG) PET
scan excluding extracardiac disease,30,31 to
more loose ones not requiring either tissue diag-
nosis32–34 or whole-body FDG-PET.5 As expected,
the range of prevalence of isolated CS is lower
with the former (from 3% to 23%),30,31 and higher
with the latter (from 9% to 65%).5,32–34
EPIDEMIOLOGY
Sarcoidosis has been shown to affect more
frequently the female gender. In a contemporary
analysis of a large US database, the annual
Fig. 1. Common locations of granuloma-
tous inflammation with their clinical im-
plications. Common locations of
granulomatous inflammation found in
the autopsy series by Roberts and col-
leagues.22 1: ventricular septum, ceph-
alad portion. 2: papillary muscles. 3: left
ventricular free wall. 4: right ventricular
free wall. 5: atrial wall. LA, left atrium;
LV, left ventricle; RA, right atrium; RV,
right ventricle; VS, ventricular septum.

incidence and prevalence of sarcoidosis were
about 8 and 60 per 100,000, respectively. Female
patients were twice more likely to develop sarcoid-
osis.35 In CS, however, a male predominance has
been demonstrated in many cohorts.36–39 In a
cohort including 1445 patients with sarcoidosis
from 10 different countries, male patients were
significantly more likely to develop CS (odds ratio
[OR] 1.33, 95% confidence interval [CI] 1.10–
1.61).39
Nonetheless, this male predominance in CS has
not been a universal finding. In a retrospective
Finnish cohort including patients with biopsy-
proven CS from 1988 to 2002, 65% of the cases
(71/110) were female.5 A similar story is observed
in Japan. After an initial report suggested similar
rates of cardiac abnormalities between male and
female patients with sarcoidosis,40 a more recent
analysis including 512 Japanese patients with CS
showed that 64% of them were female.41 The
latter study had a more rigorous guideline-based
criterion to diagnose cardiac involvement.
Sarcoidosis has also been known to more
frequently affect African Americans. In the United
States, both annual incidence and prevalence in
African Americans (17.8 and 141.4 per 100,000,
respectively) are higher than in Caucasians, His-
panics, or Asians.35 This distribution seems to be
different in CS. Many cohorts including patients
with CS have been shown a predominance of
white patients, although this could be explained
by selection bias due to health care dispar-
ities.37,38,42 Larger studies including patients with
sarcoidosis have shown no significance difference
in the rate of clinically manifest CS between Afri-
can American and Caucasian individuals.25,39,43
In a large American cohort including 1248 patients
with sarcoidosis (66% being African Americans),
cardiac involvement did not differ between races
(OR 1.29, 95% CI 0.78–2.31).43
EVALUATION
Known Extracardiac Sarcoidosis with No
Cardiac Symptoms
In patients with known extra-CS with no cardiac
symptoms, it is recommended to screen for CS.
The 2014 Heart Rhythm Society (HRS) Expert
Consensus Statement lists 2 class I recommenda-
tions: (1) to ask patients about significant palpita-
tions (ie, a prominent patient complaint lasting
more than 2 weeks), presyncope and unexplained
syncope; and (2) to obtain a 12-lead electrocardio-
gram (ECG).44
Screening with cardiac symptoms inquiry and
ECG has been shown to have a sensitivity of
69% to detect CS based on HRS criteria.27
Cardiac Sarcoidosis 3
Some ECG abnormalities have also been shown
to predict cardiovascular outcomes. In a large pro-
spective cohort from Japan including 227 patients,
11 developed cardiac events (advanced atrioven-
tricular block, ventricular tachycardia [VT], or sys-
tolic dysfunction) over 6.3  3.7 years.
Independent predictors of outcomes were heart
rate (HR 1.05, 95% CI 1.00–1.10, P 5 .03), pro-
longed PR interval (HR 11.3, 95% CI 3.27–39.03,
P < .001), right bundle branch block (RBBB) (HR
6.89, 95% CI 1.42–33.45, P 5 .02), ST-T abnor-
mality (HR 6.26, 95% CI 1.67–23.42, P 5 .006),
and fragmented QRS complex (HR 9.09, 95% CI
2.59–31.96, P < .001).45 Therefore, despite its
limited sensitivity as a screening strategy, ECG is
a simple, cheap, and widely available test that
can potentially predict clinically manifest disease.
The role of CMR in the screening process was
explored in a large Greek cohort including 321
consecutive patients with biopsy-proven extra-
CS.27 In this cohort, CMR had the highest sensi-
tivity among all tests (96%, 95% CI 91.1%–
99.4%). Delayed gadolinium enhancement on
CMR was the only independent predictor of out-
comes (HR 9.14, 95% CI 1.44–57.82, P 5 .019).
However, this predictive ability was not present
in patients without cardiac symptoms and/or
ECG abnormalities.27
Known Extra-Cardiac Sarcoidosis with New
Cardiac Symptoms
In patients with known extra-CS with new cardiac
symptoms, an evaluation for CS should start. The
first step is to recognize that the probability of
CS in these patients is high, about 39% in 2
different cohorts.27,36 Most common symptoms
are palpitations, presyncope, and syncope.27 Car-
diac involvement can manifest itself many years
after the initial sarcoidosis diagnosis.27,46 Once
CS is suspected, initial tests such as ECG, ambu-
latory ECG, and echocardiogram should be
considered.
In a Danish cohort exploring ECG abnormalities
and prognosis, 244 baseline ECG from patients
with sarcoidosis were analyzed. Thirty five (14.3%)
were abnormal, with encountered abnormalities be-
ing sinus tachycardia (17/244), incomplete RBBB
(11/244), RBBB (3/244), first-degree atrioventricular
block (1/244), premature ventricular complex (PVC)
(2/244), and ST depression (1/244). ECG abnormal-
ities were associated with higher mortality over a
median follow-up period of 27 years (range 0–
36 years), compared to no ECG abnormalities
(51% vs 28%, respectively, P < .05). This was mainly
driven by sinus tachycardia and lost its significance
when adjusted for lung function.47
4 Ribeiro Neto et al
Holter findings that are more frequent in sarcoid-
osis patients with cardiac involvement versus no
cardiac involvement are supraventricular tachy-
cardia, nonsustained VT, and frequent PVC.27,48
The sensitivity and specificity of these findings
are suboptimal, however, ranging from 59% to
64% and from 58% to 85%, respectively.27,36
Common abnormalities seen with echocardiog-
raphy in CS are LV systolic dysfunction (either by
ejection fraction [EF] or global longitudinal strain),
LV dilation, intraventricular septal thickening or
thinning, and regional wall motion abnormalities
in the absence of coronary artery disease.5,27,49
Basal thinning of the intraventricular septum,
which has been traditionally considered very spe-
cific for CS, has also been shown to be an inde-
pendent predictor of cardiac events (HR 2.95,
95% CI 1.40–6.19, P 5 .005, for a composite
outcome of mortality, heart failure admission,
symptomatic ventricular arrhythmias, and heart
block)50 and LV systolic dysfunction (HR 3.7,
95% CI 1.5–9.6, P 5 .01).51
Given the earlier autopsy series by Roberts and
colleagues22 demonstrating a common involve-
ment of the papillary muscles by granulomatous
inflammation, it is relevant to discuss a recent
American cohort exploring the mechanisms of
mitral regurgitation (MR) in CS.52 In this single-
center study including 512 patients with CS, 54
had at least moderate MR. In 34 patients with car-
diac PET scan available, 68% had FDG uptake in
the papillary muscles. After immunosuppression,
37% of patients showed improvement in the MR,
26% remained stable, and 37% got worse.
Follow-up cardiac PET scan was available in 20
patients, with resolution of the FDG uptake in
80% of them. Most patients also received
angiotensin-converting enzyme inhibitor/angio-
tensin II receptor blocker/angiotensin receptor-
neprilysin inhibitor (94%) and beta-blockers
(91%), constituting a possible confounding
factor.52
When the clinical suspicion is high enough,
either by clinical symptoms or test abnormalities,
advanced cardiac imaging should be performed.
The 2020 ATS guidelines suggests that CMR
should be obtained first because it is less expen-
sive, more widely available, less prone to false-
positive results, and has a larger body of evidence
supporting it’s prognostic ability.53 However, in
cases where a CMR cannot be obtained, or
when it is inconclusive, a cardiac PET scan should
be performed.53 Moreover, data suggest that
obtaining both CMR and cardiac PET scan can
improve diagnostic accuracy.54
Cardiac MRI can detect important findings such
as regional wall motion abnormalities, aneurysms,
wall thinning or thickening, delayed gadolinium
enhancement (DE), or abnormal tissue signal char-
acteristics on T2-weighted imaging suggestive of
underlying edema/inflammation (Fig. 2).55–57 DE
occurs in a nonischemic distribution and often in-
volves noncontiguous regions of increased signal
in various distributions, which can be transmural,
subendocardial, mid-myocardial, or epicardial.
An early report suggested a predilection for the
basal and midventricular septum, although any
myocardial segment can be involved.55 A more
contemporary and larger cohort confirmed that
the septum was most commonly involved (71%
out of 321 patients), followed by the LV lateral
wall (52%), anterior wall (22%), inferior wall
(17%), and RV (8%).27 Careful evaluation of DE im-
ages can also demonstrate enhancement of papil-
lary muscles, as described above. The diagnostic
accuracy of CMR has been evaluated by many
studies, and recently reviewed in a systematic re-
view and meta-analysis.58 The pooled sensitivity
was 95% (95% CI 90%–98%) and the pooled
specificity was 85% (95% CI 67%–95%). A sepa-
rate systematic review and meta-analysis
including 13 studies and 1318 patients showed
that DE was associated with all-cause mortality
(OR 3.45, 95% CI 1.6–7.3) and ventricular arrhyth-
mias (OR 20.3, 95% CI 8.1–51.0). Biventricular DE
was associated with ventricular arrhythmias (OR
43.6, 95% CI 16.2–117.2). The annualized inci-
dence of all-cause mortality was 5% in patients
with DE, compared to 1% in patients with no DE
(P < .05). The annualized incidence of ventricular
arrhythmias was 6.7% in patients with DE,
compared to 0.04% in patients with no DE
(P < .001).59
Finally, a comprehensive study demonstrated
that different DE patterns carry different progno-
ses. This American cohort included 504 consecu-
tive patients with biopsy-proven sarcoidosis and
stratified the DE pattern as pathology-frequent
(LV subepicardial, LV multifocal, septal, and/or
RV free wall involvement) or pathology-rare (any
other DE pattern) phenotypes. In multivariable
analysis, pathology-frequent DE, compared to
pathology-rare DE, was predictive of both arrhyth-
mias (HR 12.12, 95% CI 3.62–40.57, P < .001) and
heart failure (HR 2.49, 95% CI 1.19–5.22, P 5 .02)
events. Extent of LV DE was also predictive of ar-
rhythmias (HR 1.04, 95% CI 1.01–1.07,
P 5 .003).60
Cardiac PET scan evaluates the myocardium
metabolism (typically with FDG) and perfusion
(typically with rubidium-82 or N13-ammonia)
(Fig. 3). Depending on the combination of these
2 variables, the results can be normal (normal
perfusion with no FDG uptake), consistent with
 Cardiac Sarcoidosis 5

Fig. 2. Cardiac MRI findings in 2 patients with cardiac sarcoidosis. (A, B) Phase sensitive inversion recovery (PSIR)
delayed enhancement imaging of the left ventricle 4-chamber (left) and 3-chamber (right views), showing patchy,
mid-myocardial delayed enhancement particularly involving the septum (arrows). The noncontiguous pattern of
enhancement is nonischemic and consistent with cardiac sarcoidosis (patient 1). (C–E) Delayed enhancement im-
aging shows focal increased signal isolated to the right ventricular and mid-myocardial aspects of the basal to
mid inferoseptum and inferior wall (arrows). Focal disease in this region is typically associated with conduction
block due to the anatomic location of the conduction system (patient 2).

scar tissue or match defect (abnormal perfusion
with no FDG uptake), consistent with advanced
inflammation or mismatch defect (abnormal perfu-
sion and FDG uptake), or suggestive of early
stages of inflammation (normal perfusion with
FDG uptake).61 In this latter scenario, however,
failure to suppress the myocardium glucose up-
take or normal variants should be considered.61
A strict low carbohydrate diet at least the day
before followed by 12 h of fasting before the test
is essential for a good quality cardiac PET
scan.62,63 Intravenous heparin at 50 IU/kg 15 min
before FDG administration can also facilitate this
glucose uptake suppression.64 Importantly, a
diffuse or LV lateral wall FDG uptake pattern has
been demonstrated in healthy volunteers, which
could represent a normal variant.65
The diagnostic accuracy of cardiac PET scan
has also been evaluated in many studies, and a
recent systematic review and meta-analysis
included 32 of them.58 The pooled sensitivity was
84% (95% CI 74%–90%), and the pooled speci-
ficity was 82% (95% CI 75%–88%). Most of the
studies considered the focal and focal-on-diffuse
patterns positive for CS, and the no uptake and
diffuse uptake patterns negative for CS.58
The first study to evaluate the prognostic ability of
cardiac PET scan was an American cohort
including 118 consecutive patients with known or
suspected CS. Independent predictors of death or
VT were EF (HR 0.78, 95% CI 0.63–0.98, P 5 .04),
RV FDG uptake (HR 2.82, 95% CI 1.03–7.60,
P 5 .042), abnormal perfusion and metabolism
(HR 2.87, 95% CI 1.05–7.85, P 5 .039), and
6 Ribeiro Neto et al

Fig. 3. Cardiac PET scan findings in 3 patients with cardiac sarcoidosis. (A) Moderate amount of scar involving the
basal to mid-anterior segments and mid-inferoseptal to inferior segments. Large area of increased 18F-FDG signal
involving the basal septum, lateral wall, and apical anterior and lateral segments. Mismatch pattern with
decreased perfusion and increased F18-FDG involving the lateral wall (arrows) (patient 1). (B) Focal increase in
F18-FDG signal involving basal septum extending into basal inferior left ventricular myocardium (patient 2).
(C, D) Increased F18-FDG signal involving the basal anteroseptum (C), apical lateral and mid-inferolateral seg-
ments extending into the adjacent papillary muscles (D) (patient 3). F18-FDG: 18F-fluorodeoxyglucose.

abnormal perfusion or metabolism (HR 2.44, 95% Patients with Cardiac Manifestations and
CI 0.90–6.66, P 5 .08).19 Isolated FDG uptake of Suspected Cardiac and Extra-Cardiac
the LV lateral wall was not predictive.19 Subsequent Sarcoidosis
studies were summarized in a recent systematic re-
In patients with cardiac manifestations and sus-
view and meta-analysis, corroborating those re-
pected cardiac and extra-CS, tissue diagnosis
sults. Predictors of major adverse cardiovascular
should be pursued from the most feasible target.
outcomes were abnormal PET LV findings (RR
Cutaneous lesions could be potential targets, as
2.08, 95% CI 1.48–2.92) across 6 studies and
an European multicenter study identified a cluster
abnormal PET RV findings (RR 2.96, 95% CI
of organ involvement that included ocular, cardiac,
1.12–7.78) across 3 studies.66 A retrospective
cutaneous ,and central nervous system.68
study, however, analyzed FDG uptake separately
A whole body PET scan should always be per-
from perfusion defects and did not find isolated
formed when evaluating these patients.69,70 A
FDG uptake to be predictive of outcomes.67

Canadian prospective study including 31 patients
with suspected CS showed that 30 of them had
signs of extra-CS in the whole body PET scan,
with pulmonary sarcoidosis being the most com-
mon one.69 Similar findings were seen in a subse-
quent retrospective Finnish cohort, where 39 out
of 57 consecutive patients with CS had signs of
extra-cardiac disease on whole-body PET. Pulmo-
nary sarcoidosis was once again the most com-
mon one.70 Regardless of how high the pre-test
probability for sarcoidosis may be in these cases,
there are currently no studies identifying a sub-
group of patients in whom a biopsy is not required
to confirm the diagnosis.
In a multicenter retrospective cohort study from
the United States, 37 patients with suspected CS
underwent bronchoscopy. In 25 patients with
abnormal chest computed tomography (CT), 10
patients were diagnosed with biopsies or needle
aspirations, and 8 patients with bronchoalveolar
lavage.71 A smaller single-center retrospective
American cohort included 15 patients with sus-
pected extrapulmonary sarcoidosis (5 of them car-
diac) with normal chest CT that underwent
bronchoscopy. Despite the small lymph nodes,
they were FDG avid 6 patients, 4 of which had
endobronchial ultrasound-guided transbronchial
needle aspiration (EBUS-TBNA) compatible with
sarcoidosis.72
Patients with Cardiac Manifestations and
Suspected Isolated Cardiac Sarcoidosis
This is arguably the most challenging of the 4
groups. In patients with cardiac manifestations
and suspected isolated CS, a multidisciplinary dis-
cussion should guide decision-making.73,74 A
bronchoscopy is a reasonable next step in trying
to obtain tissue diagnosis, since it has been shown
to be diagnostic in a small number of cases with no
signs of pulmonary sarcoidosis on chest CT and
PET scan.71,72 If bronchoscopy is nondiagnostic
or not done, an endomyocardial biopsy should
be considered.
The sensitivity of endomyocardial biopsy for CS
is low, around 20% to 30%.75,76 This sensitivity
can be increased with repeated sessions, cardiac
imaging guidance, or electrogram guidance.77–79
The overall rate of major complication is low (about
1%), and includes cardiac perforation or tampo-
nade (more common with RV biopsies), and stroke
or systemic embolism (more common with LV bi-
opsies).76 In experienced centers, it is an impor-
tant tool in the clinicians’ armamentarium.
In possible isolated CS, special attention needs
to be paid to differential diagnoses. Genetic car-
diomyopathies have been increasingly recognized
Cardiac Sarcoidosis 7
as potential mimickers of isolated CS. In an Amer-
ican cohort including 94 patients referred for
advanced cardiac imaging for suspected CS, 6 in-
dividuals had variants associated with dilated car-
diomyopathy.80 A second cohort from the United
States including 110 patients with suspected iso-
lated CS, 14 had genetic testing. Of those, 5 had
pathogenic variants and abnormal cardiac PET
scans.81 Similarly, in a cohort with 107 patients
with desmoplakin cardiomyopathy, 4 patients
had abnormal cardiac PET scans and were mis-
diagnosed with either myocarditis or CS.82 There-
fore, we recommend genetic testing in patients
with suspected isolated CS. Other important dif-
ferential diagnoses are shown in Table 1.
THERAPEUTIC OPTIONS
Immunosuppressive Therapy
Therapeutic options can be divided into immuno-
suppressive agents, guideline-directed medical
therapy (GDMT), antiarrhythmic medications, de-
vice/ablation therapy, and heart transplantation.
Regarding immunosuppression, the first point to
recognize is that not every patient with CS needs
it. In a large American cohort including 1582 pa-
tients with sarcoidosis, 74 had cardiac involve-
ment and 46 of them (62%) required treatment.43
The recent 2021 European Respiratory Society
guidelines on treatment of sarcoidosis strongly
recommend using immunosuppression in patients
with clinically relevant CS.83 In patients with clini-
cally silent disease, it is reasonable to stratify risk
and guide treatment decisions using longitudinal
follow-up and the prognostic variables mentioned
in prior sections of this article.
Another guiding principle should be the likelihood
of a patient to respond to immunosuppression,
based on clinical manifestation. Heart block is the
most likely manifestation to respond to immuno-
suppression, with a response rate of about
43%.16 Therefore, a trial of immunosuppression is
reasonable in these patients regardless of other
findings. There are conflicting data in the literature
regarding the response rate of ventricular arrhyth-
mias.16 Therefore, it is reasonable to use the pres-
ence or absence of FDG uptake on cardiac PET
scan to help guide immunosuppressive therapy in
this scenario. In patients with heart failure,
advanced cardiac imaging can also be used to
guide decision-making. An Indian cohort including
96 consecutive patients with CS showed a strong
positive correlation between cardiac PET scan
FDG uptake index (product of maximum LV
myocardial uptake and the number of LV segments
with abnormal uptake) and improvement in LVEF
(R 5 0.887, P < .001).84 In contradistinction, a
8 Ribeiro Neto et al

Table 1
Selected differential diagnoses in suspected isolated cardiac sarcoidosis

Differential Diagnosis Comments

Ischemic heart disease Ischemia can increase glucose utilization by the
myocardium, leading to FDG uptake on PET
Inflammatory cardiomyopathies
Giant cell myocarditis Fulminant course of left-sided heart failure,
infrequent heart block, poor prognosis
Lymphocytic myocarditis Variable clinical course, treatment with
immunosuppression is debatable
Infectious myocarditis
Viruses, bacteria (eg, Borrelia burgdorferi, Presence of infectious symptoms, travel history
Treponema pallidum, Tropheryma to endemic areas, history of tick bite; infection
whipplei), mycobacteria (eg, Mycobacterium work up depending on clinical suspicion
tuberculosis), fungi (eg, Aspergillus
fumigatus), parasites (eg, Trypanosoma cruzi)
Genetic cardiomyopathies
ARVC, LMNA, TTN 2, JPH2, TPM1, MYBPC3, DSP Family history and genetic testing should be
obtained. Diagnostic criteria are available
for ARVC
Malignancy
Primary cardiac lymphoma Intracardiac mass, usually affecting right heart
chambers and pericardium

Abbreviations: ARVC, arrhythmogenic right ventricular cardiomyopathy; DSP, desmoplakin; FDG, fluorodeoxyglucose;
JPH2, junctophilin 2; LMNA, lamin A/C; MYBPC3, myosin binding protein C; TPM1, tropomyosin 1; TTN, titin.

Japanese cohort including 43 consecutive patients
with CS showed a negative correlation between
percent DE in CMR and improvement in LVEF
(R2 5 0.38, P < .01).85 It is important to recognize
that, unlike ischemic heart disease, DE does not un-
equivocally connote irreversible scarring.
Once a decision is made to treat it with immuno-
suppression, corticosteroids are currently the first-
line agents. Treatment should be initiated as soon
as possible, as there is evidence linking early ther-
apy (ie, within a month of diagnosis) with improve-
ment in EF.86 The optimal initial dose is not well
known, with prednisone dose ranging in a recent
systematic review from 20 to 60 mg daily, tapered
over a 6 month period, until a maintenance dose of
5 to 10 mg daily. In that systematic review, which
included 21 studies and 950 patients, most pa-
tients (709) were treated with corticosteroids
monotherapy.87
Combined therapy with corticosteroids and
nonsteroidal immunosuppressive agents was
associated with a reduced maintenance dose of
corticosteroids in a separate systematic review
that included 23 studies and 480 patients.88 The
most common nonbiologic immunosuppressant
used was methotrexate, with other reasonable
second-line options being mycophenolate mofetil,
azathioprine, and leflunomide. The most common
biologic used was infliximab, with adalimumab be-
ing used in many studies as well. Examples of
other agents used were rituximab and cyclophos-
phamide, which are possible options in refractory
cases.88 Future randomized controlled trials will
hopefully answer many of the questions related
to which medication to use and when.
Guideline-Directed Medical Therapy and
Antiarrhythmic Medications
In patients with CS presenting with heart failure
with reduced EF, GDMT should be used.89 Antiar-
rhythmic medications are important in patients
with CS to control arrhythmias and improve symp-
toms.90 Some examples of antiarrhythmic medica-
tions used in CS are amiodarone, mexiletine, and
sotalol.44,90 A recent American retrospective
cohort including 42 patients with CS showed a
better arrhythmic control with combined immuno-
suppression and antiarrhythmic medications,
compared with either immunosuppression or anti-
arrhythmic medications alone.91
Device/Ablation Therapy
Decisions regarding device implantation need
to be made in conjunction with an electrophysiolo-
gist and directed by guidelines.44,90 Class I
 Cardiac Sarcoidosis 9

recommendations for an implantable cardioverter-
defibrillator (ICD) are prior sustained ventricular ar-
rhythmias or cardiac arrest and EF  35%.44,90 An
ICD can also be useful in the following situations:
indication for pacemaker, unexplained syncope
or near syncope, inducible ventricular arrythmias,
or DE in the CMR.44,90 Predictors of ventricular ar-
rhythmias mentioned in prior sections can help in
this decision process. If an ICD is indicated, pa-
tients should receive at least a dual-chamber de-
vice to improve atrioventricular synchrony in
case heart block develops.44 A third lead in the
LV can be placed if there is indication for cardiac
resynchronization therapy.89
Catheter ablation is an option for patients with re-
fractory ventricular arrhythmias in CS. An American
cohort used propensity score analysis to compare
patients with CS who had undergone ablation
versus those with ICD placement only with no abla-
tion. In 20 patients with CS, ablation sessions were
successful in 14 (70%). However, the number of
appropriate ICD therapies increased significantly
after 12 months in the ablation group.92 A recent
systematic review and meta-analysis including 15
studies and 401 patients showed a success rate
of 57%, with low (5.7%) procedure-related compli-
cations. However, VT recurred after first ablation in
55% (95% CI 48%–63%) of the patients.93

Table 2
Differences between guidelines

2014 HRS 2014 WASOG 2016 JCS: Nonisolated 2016 JCS: Isolated
Abnormal cardiac PET Yes Yes Yes Yes
Delayed enhancement on Yes Yes Yes Yes
cardiac MRI
Unexplained VT Yes Yes Yes Yes
High grade AV block Yes Yes Yes Yes
Reduced EF Yes (<40%) Yes Yes Yes (<50%)
Biopsy proven sarcoidosis Yes Yes Yes No
required for diagnosis
Treatment responsive Yes Yes No No
cardiomyopathy
Gallium uptake scan Yes Yes Yes Yes
Ventricular fibrillation No No Yes Yes
Perfusion scintigraphy OR No Yes Yes No
SPECT scan
T2 prolongation on No Yes No No
cardiac MRI
Basal thinning of the No No Yes Yes
ventricular septum OR
abnormal ventricular
wall anatomy
Abnormal ECG findings: No No Yes No
ventricular arrhythmias
(NSVT, multifocal or
frequent PVCs), bundle
branch block, axis
deviation, or
abnormal Q waves
Endomyocardial biopsy: No No Yes No
monocyte infiltration
and moderate or
severe myocardial
interstitial fibrosis.

Abbreviations: AV, atrioventricular; ECG, electrocardiogram; EF, ejection fraction; HRS, Heart Rhythm Society; JCS, Japa-
nese Circulation Society; MRI, magnetic resonance imaging; NSVT, nonsustained ventricular tachycardia; PVC, premature
ventricular contraction; SPECT, single photon emission computed tomography; VT, ventricular tachycardia; WASOG,
world association for sarcoidosis and other granulomatous disorders.
10 Ribeiro Neto et al
Heart Transplantation
Many cohort studies have demonstrated good
outcomes post-heart transplant in patients with
CS.94–96 Two studies using the United Network
for Organ Sharing (UNOS) registry evaluated
more than 30 years of data and showed that pa-
tients transplanted for CS had similar survival
and risk of graft failure compared to non-CS pa-
tients.94,96 A separate study analyzing more recent
data since 1999 showed a better 10 year survival
rate in patients transplanted for CS compared to
other indications (73.4% [95% CI 64.2%–80.6%]
vs 59.5% [95% CI 58.8%–60.1%], P 5 .002).95
CS recurrence after transplant happens in about
10% of the patients, but it’s usually an incidental
finding in routine endomyocardial biopsies with
no clinical implication.97 Left ventricular assist de-
vice has been increasingly used in patients with
CS and advanced heart failure, with similar out-
comes compared to non-CS patients.98
Guidelines
Many important guidelines can assist patient care.
The 2014 HRS guidelines explore diagnosis,
screening, and management.44 The 2014 World
Association for Sarcoidosis and Other Granuloma-
tous Disorders (WASOG) document on organ
manifestations can also guide diagnosis,99 and it
has been shown to have high concordance with
the HRS criteria (kappa 5 1).37 The new 2016 Jap-
anese Circulation Society guidelines is the first one
to include criteria for isolated CS without the need
for tissue diagnosis.100 Unsurprisingly, it has been
shown to have low concordance with the WASOG
and HRS criteria (kappa 5 0.326).37 All 3 criteria
still require further validation in prospective studies
against patient-important outcomes. Table 2 high-
lights important differences between these
guidelines.
CLINICS CARE POINTS
 Granulomatous inflammation in CS can affect
any portion of the heart, causing clinical
manifestations such as atrioventricular block,
heart failure, and ventricular arrhythmias.
 In patients with known extra-CS and no car-
diac symptoms, screening for CS should
include questions about palpitations, unex-
plained presyncope and syncope, and an ECG.
 In patients with known extra-CS with new
cardiac symptoms, initial tests such as ECG,
ambulatory ECG, and echocardiogram should
be considered; when the clinical suspicion is
high enough, either by clinical symptoms or
test abnormalities, advanced cardiac imaging
should be performed to confirm the diag-
nosis of CS.
 In patients with cardiac manifestations and
suspected cardiac and extra-CS, tissue diag-
nosis should be pursued from the most
feasible target.
 In possible isolated CS, special attention
needs to be paid to differential diagnoses.
DISCLOSURE
Nothing to disclose.
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