Author’s Accepted Manuscript

Cardiac Sarcoidosis: A Review of Contemporary

Challenges in Diagnosis and Treatment

Yan Yatsynovich, Nathaniel Dittoe, Mikhail

Petrov, Natallia Maroz

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PII: S0002-9629(17)30463-9
DOI: http://dx.doi.org/10.1016/j.amjms.2017.08.009
Reference: AMJMS524
To appear in: The American Journal of the Medical Sciences
Received date: 6 June 2017
Revised date: 11 August 2017
Accepted date: 16 August 2017
Cite this article as: Yan Yatsynovich, Nathaniel Dittoe, Mikhail Petrov and
Natallia Maroz, Cardiac Sarcoidosis: A Review of Contemporary Challenges in
Diagnosis and Treatment, The American Journal of the Medical Sciences,
http://dx.doi.org/10.1016/j.amjms.2017.08.009
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Title: Cardiac Sarcoidosis: A Review of Contemporary Challenges in Diagnosis and Treatment
Authors: Yan Yatsynovich M.D.1, Nathaniel Dittoe M.D.1,2,3, Mikhail Petrov M.D.4 , Natallia
Maroz M.D.1,3,5
1
Kettering Medical Center, Department of Medicine, Dayton, Ohio, United States
2
Kettering Medical Center, Department of Medicine, Cardiology Section, Dayton, Ohio, United
States
3
Wright State University, Boonshoft School of Medicine, Department of Medicine, Dayton,
Ohio, United States
4
Norwalk Hospital, Department of Medicine, Norwalk, Connecticut, United States
5
Renal Physicians Inc., Dayton, Ohio, United States
Corresponding Author:
Yan Yatsynovich, MD
Kettering Medical Center
Department of Internal Medicine
3535 Southern Boulevard
Dayton, OH 45429
United States
Telephone: (716) 866-1525
Fax: (937) 395-8399
yan.yatsynovich@ketteringhealth.org

Short Title: Cardiac Sarcoidosis: Contemporary Challenges in Diagnosis and Treatment

Conflicts of Interest: the authors have no conflicts of interest to disclose

Authorship declaration: All authors listed meet the authorship criteria according to the latest
guidelines the International Committee of Medical Journal Editors. All authors are in agreement
with the manuscript.

Acknowledgements: None

Source of Funding Statement: No financial support or interest to be declared

1
Key Words: cardiac sarcoidosis, non-invasive imaging, late gadolinium enhancement,
endomyocardial biopsy, immunosuppressive therapy
List of Abbreviations:
18F-FDG PET - 18F-Fluorodeoxyglucose Positron Emission Tomography
67-Ga - Gallium-67
201-Th - Thallium-201
ACCESS - A Case Control Etiologic Study of Sarcoidosis
ACE - angiotensin-converting enzyme
ARB - angiotensin receptor blocker
ARVC - arrhythmogenic right ventricular cardiomyopathy
AV - atrioventricular (block)
CMR - cardiac magnetic resonance imaging
CRT - cardiac resynchronization therapy
CS - cardiac sarcoidosis
CV-IB - Cycle dependent variation of myocardial integrated backscatter
ECG - electrocardiogram
EMB - endomyocardial biopsy
EP mapping - electrophysiological mapping
HLA - Human leukocyte antigen
HRS - Heart Rhythm Society
ICD - implantable cardioverter-defibrillator
IL-2 - interleukin 2
JMHW - Japanese Ministry of Health and Welfare
LGE - late gadolinium enhancement
PET - Positron Emission Tomography
RFA - radiofrequency ablation
TWAaVR - T-wave amplitude in lead aVR
VT - ventricular tachycardia
VF - ventricular fibrillation
WASOG - World Association for Sarcoidosis and Other Granulomatous Disorders

2
Abstract

Sarcoidosis is a systemic disease characterized by noncaseating granulomas and is often a

diagnosis of exclusion. The actual prevalence of cardiac sarcoidosis (CS) is unknown, as studies

have demonstrated mixed data. CS may be asymptomatic and is likely more frequently

encountered than previously thought. Sudden death may often be the presenting feature of CS.

Most deaths attributed to CS are caused by arrhythmias and/or conduction system disease and

congestive heart failure may occur. Current expert consensus on diagnosis of CS continues to

rely on endomyocardial biopsy, in the absence of which, histological proof of extracardiac

sarcoid involvement is necessitated. Emergence of newer non-invasive imaging modalities such

as cardiac magnetic resonance imaging (CMR) and positron emission tomography (PET), have

become increasingly popular tools utilized in patients with both clinical and asymptomatic CS,

and have demonstrated good diagnostic capability. The main therapeutic approaches in

patients with CS can be broadly divided into two categories: pharmacological management and

invasive/device oriented. However, much remains unknown about the optimal screening

protocols of asymptomatic patients with extracardiac sarcoidosis and treatment of biopsy-

proven CS. Our knowledge about CS has amplified significantly over the last 30 years and the

growing realization that this process is often asymptomatic, is paving the way for better

screening protocols and earlier detection of this serious condition.

3
A. Introduction and Background

Sarcoidosis is a multi-organ disease that is histologically characterized by presence of

noncaseating granulomas. It is often a diagnosis of exclusion, as other conditions such as

mycobacterial and fungal infections, malignancy, and environmental etiologies may also be

associated with a similar granulomatous process. It can affect any organ system in the body

with the pulmonary manifestations present in more than 90% of cases [1]. Involvement of other

organs such as the heart, liver, kidney, eyes, and skin, has been documented but is not as

commonly encountered. In the ACCESS study of 736 patients, 95% had lung involvement, 24%

had skin signs, 15% had involvement of the extra-thoracic lymph nodes and only 2%

demonstrated cardiac manifestations [2]. To the contrary, a Japanese sarcoidosis cohort

reported development of cardiac involvement in approximately 25% of patients, in contrast to

only a 2-7% reported prevalence in both United States and Europe [3].

The etiology of the sarcoid disease process still remains unknown. Recent studies have

identified potential triggers mentioned previously, which in genetically susceptible hosts, may

trigger an inflammatory cascade resulting in activation of this disease process. Studies have

clarified that specific haplotypes, such as HLA-DRB1*1101 and HLA-DRB1*0101 are associated

with increased lifetime risk for developing sarcoidosis [4]. Associations have also been noted

with HLA-DQB*0601 and tumor necrosis factor allele TNF-A2 [5, 6].

4
Worldwide, the highest prevalence of sarcoidosis has been found among the Northern

European population. In United States, it is typically found in women of African American

descent, although all genders and races can be affected by this disorder [7].

Compelling advances in imaging over the last two decades have re-shaped the recognition and

understanding of cardiac sarcoidosis (CS). It is often asymptomatic and likely more frequently

encountered than previously thought. Formerly, emphasis has focused on tissue specimens for

diagnosis. While an endomyocardial biopsy can definitively establish such case, its sensitivity is

low, given the patchy distribution of disease involvement of the myocardium [8, 9]. As a result,

advanced imaging modalities have become prominent in the diagnosis and management of CS.

B. Epidemiology of Cardiac Sarcoidosis

Historical Perspective

The first pathological depiction of CS, published in 1929, described novel findings unexpectedly

discovered during a postmortem examination [10]. Several years later, Jörgen Nilsen

Schaumann, whose namesake has been given to Schaumann bodies, had demonstrated CS

involvement in another two autopsies [11]. The first attributed death in a patient with known

diagnosis of CS was reported in 1937 [12]. Throughout the 1960’s-1970’s, more autopsy studies

5
of patients with known extracardiac sarcoidosis have demonstrated cardiac involvement and

provided descriptions of both clinical and pathological features of CS [13-17]. Until the 1980's

and even recently, literature reports were mainly limited to isolated descriptions of the disease,

but in the last decade, awareness of CS has increased dramatically. Newer, non-invasive

imaging modalities pioneered detection of CS in asymptomatic individuals with sarcoidosis. For

instance, a Finnish cohort of 110 patients pointed to a marked increase in recognition of CS

(greater than 20-fold) with contemporary diagnostic modalities [18].

A 2017 review of PubMed database had demonstrated a nearly threefold spike in sarcoidosis

publications beginning 2010 (Figure 1), particularly cardiac involvement, thereby reflecting

increased awareness of this not yet completely understood disease process.

Prevalence

The actual prevalence of CS is not known as studies have demonstrated mixed data. The highest

rates of cardiac involvement, up to 78%, were found in autopsy series of patients with known

sarcoidosis (15). Japanese pathologists have reported higher rates of cardiac involvement in

comparison to their colleagues across the globe [19, 20].

6
In Europe and the United States, clinical manifestations of CS have been described in as little as

2% to 7% of patients [2, 21], and as high as 73% in whites and 23% in African-American or

Caribbean patients [22]. Newer imaging techniques have contributed to increasing prevalence

of CS. Cardiac involvement was identified in nearly 25% of patients with biopsy-proven

extracardiac sarcoidosis screened with cardiac MRI in Poland [21]. That prevalence correlated

with the study of 84 autopsied sarcoidosis patients where a small, anatomically restricted area

of affected myocardium has been found in at least 25% of those who were clinically silent (i.e.

no cardiac manifestations) [16].

Although there is little information on its incidence or significance, presence of CS is strongly

associated with poorer outcomes. In most instances, cardiac involvement remains subclinical,

although cardiac manifestations may occur in the absence of systemic involvement.

Unfortunately, in many cases of sudden cardiac death diagnosis of CS is established post-

mortem. Unrecognized CS remains a leading cause of death in patients with sarcoid disease,

with attributable mortality rates 50-85% in an autopsy series [17, 23, 24] and reported 60%

survival at 5 years and 44% at 10 years by Japanese cohorts [20, 25].

7
C. Clinical Manifestations

Clinical manifestations of CS are influenced by the anatomical location, as well as the extent

and activity of disease. While arrhythmias and conduction defects are most frequently

encountered, progressive heart failure from granulomatous infiltration of the myocardium may

account for at least 25% of deaths [15-17, 26]. Cardiac symptoms may predominate in patients

with no other clinical manifestations of extracardiac disease, including low-grade pulmonary

involvement. Alternatively, if the cardiac involvement is subclinical, patients may present with

atypical chest pain or progressive dyspnea (exertional or stationary), often as a result of

pulmonary involvement [27]. It is important to realize that CS is not bound anatomically to any

particular region of the heart, therefore it can present in a variety of ways. Most often

sarcoidosis affects the conduction system and the myocardium.

Valvular dysfunction from direct involvement of the valvular apparatus is uncommon and direct

involvement has been documented in less than 3% of cases [23]. If present, it often manifests

as mitral valve regurgitation (MR), which can be defined as primary (due to abnormalities of the

valve apparatus) or secondary (extra-valvular causes). In CS, primary MR is often due to

granulomatous infiltration of the papillary muscles. Secondary MR commonly results from left

ventricular dilation and architectural changes. Mitral valve geometry can be affected by these

8
changes resulting in impaired leaflet coaptation.

Myocardial involvement is typically patchy in nature and can present as either a localized

hypertrophy of the myocardium or a wall motion abnormality in the form of a focal dyskinesia

or hypokinesia. On a histological level, myocardial lesions contain areas of active

granulomatous inflammation that are surrounded by secondary or reactive edema [16-17, 24,

26]. As the myocardial infiltration continues, scarring and remodeling begin to replace the site

of the active granulomatous inflammation. This process may result in dilation of ventricular

cavities, local wall motion abnormalities and even aneurysm formation that results from

progressive thinning of the myocardial muscle. When involvement is diffuse, patients may

present with evidence of biventricular chamber dilation and symptoms of advanced heart

failure (Figure 1). These structural changes may also serve as subsets for arrhythmogenic foci

and make individuals more prone to development of arrhythmias, and can even clinically mimic

arrhythmogenic right ventricular cardiomyopathy (ARVC) [28].

The involvement of cardiac conduction system is most commonly found in the interventricular

septum, producing a variety of arrhythmias. These include bradyarrhythmias, tachyarrhythmias

and varying degrees of atrioventricular (AV) block. Malignant arrhythmias such as ventricular

tachycardia or ventricular fibrillation, may lead to the sudden cardiac death. As mentioned

9
previously, conduction disturbances are thought to be a result of scar formation, which

functions as an arrhythmogenic substrate through a macro-re-entry mechanism.

Infiltration of the pericardium is uncommon but may result in clinically recurrent pericardial

effusions. As a result of these recurrent insults to the pericardium, constrictive pericarditis may

develop and has been reported in some cases [29].

D. Diagnosis

CS is generally not recognized antemortem and sudden death may often be the presenting

feature. Most deaths attributed to CS are caused by arrhythmias and/or conduction system

disease, but granulomatous infiltration of the myocardium, causing progressive congestive

heart failure has been encountered and may lead to fatal outcomes. The definitive diagnosis of

isolated CS can be technically difficult. The yield of endomyocardial biopsies (EMB) is low and as

many as two-thirds of patients remain undiagnosed after their first EMB [30]. The need for

alternative diagnostic methods has paved the way for advanced cardiac imaging to become

integral to the diagnosis [31].

10
Criteria for diagnosis of CS have been presented by many international societies and the

optimal diagnostic algorithm is still in question. Historically, the first diagnostic guidelines for CS

were written by the Japanese Ministry of Health and Welfare (JMHW) in 1993. These guidelines

were revised in 2006, including the use of newer non-invasive diagnostic techniques. The

JMHW guidelines, at their core, stress on the importance of tissue for diagnosis of cardiac

involvement, with an EMB demonstrating direct cardiac infiltration. However, they also do

explore the option of clinical diagnosis from a combination of major and minor criteria (Table

1). However, JMHW recommendations have shown many limitations in regards to their

implementation in contemporary clinical practice. The typical myocardial involvement in CS is

of patchy nature, and when combined with limitations of current sampling techniques, many

patients have unremarkable initial biopsies [8]. EMB, therefore, has a low sensitivity for the

diagnosis of CS. Furthermore, the criteria still considers the inclusion of Gallium-67 (67Ga)

uptake as a major diagnostic factor, which is currently no longer performed at most centers due

to its limited diagnostic accuracy, as demonstrated by numerous studies [8, 32-34]. Most

importantly, the JMHW diagnostic criteria has neither expanded upon, nor fully implemented

the use of contemporary imaging modalities, namely cardiac magnetic resonance imaging -

CMR (included as minor criteria) and 18F-Fluorodeoxyglucose positron emission tomography -

18F-FDG PET (not included as a part of diagnostic criteria), which have shown higher diagnostic

accuracy in clinical diagnosis of CS [8, 35-37].

11
North American societies have developed their own sets of diagnostic criteria for CS. In 1999,

the United States National Institutes of Health had proposed their initial algorithm [38], which

later served as a foundation for criteria developed by the World Association for Sarcoidosis and

Other Granulomatous Disorders (WASOG) in 2014 [8, 39]. The American guidelines have

succeeded in incorporating contemporary imaging modalities and stressing their importance as

a supplement to diagnosis of CS. A recent consensus statement from the Heart Rhythm Society

(HRS) released in 2014 had reviewed and explicated the WASOG recommendations, providing

an updated set of clinical criteria for the diagnosis of CS (Table 2). Notably, CMR abnormalities

have been included as a criterion for diagnosis of CS in patients with known extracardiac

disease.

Much debate still remains about the optimal diagnostic criteria for patients with suspected CS.

The HRS consensus acknowledged difficulties in diagnosing CS, particularly in patients with

isolated (cardiac) form of the disease. While an EMB remains the gold standard for diagnosis

across all current international society recommendations, in the absence of a diagnostic EMB,

histological proof of extracardiac sarcoid involvement is advantageous. However the

applications of these algorithms in patients with clinically isolated CS are limited. With such

12
limitations, the diagnostic and therapeutic algorithms for CS remain discordant in their

approaches [8, 9, 39, 40]. Many recently published studies have further validated efficacy and

accuracy of noninvasive imaging and tests. This will hopefully guide future diagnostic

approaches in and allow use of these modalities to become an integral part of CS diagnosis.

Current screening recommendations were proposed by HRS consensus and had focused on

patients with known biopsy-proven extracardiac sarcoidosis (Table 3). Initial history,

electrocardiogram (ECG), and echocardiogram, may be done to evaluate for clinically silent

cardiac involvement, even though no large-scale studies have been yet done to define

sensitivity and specificity of various screening strategies/tests [40]. In addition, data remains

incomplete, as only few small-scale studies have been done to compare these screening

strategies. The authors of HRS guidelines also noted that patients with initial negative workup

could be re-screened if the patient develops new cardiac signs or symptoms. In the case of

patients with specific cardiac presentations, such as high-grade block, an algorithm has been

proposed [40].

13
Serum Biomarkers

Historically, angiotensin-converting enzyme (ACE) levels have been used in diagnosis of

sarcoidosis but their implication in CS is questionable. ACE levels have been found to be

elevated in 60% of patients with sarcoidosis but unfortunately lack both sensitivity and

specificity when it comes to diagnosis [41]. Neopterin and interleukin-2 (IL-2) receptor levels

have been shown to be significantly elevated in active disease [41]. Another study explored the

role of highly sensitive troponin levels in patients with newly diagnosed CS, noting that troponin

levels correlated with positive response to glucocorticoid therapy [42]. Initial studies are

promising, although none of these biomarkers have been specifically validated for clinical use in

CS.

Electrocardiogram

An electrocardiogram (ECG) is an inexpensive and readily available initial screening test for

patients with confirmed or suspected cardiac involvement. The spectrum of abnormalities

ranges from conduction disturbances to non-specific ST and T-wave changes. Japanese authors

have observed pathological ECG changes in 22% among 963 patients with sarcoidosis [43].

Another study conducted in England had detected 45% ventricular arrhythmias, 38%

conduction disturbances and 28% supraventricular arrhythmias [26]. Recently, the bundle
14
branch block and T-wave amplitude in lead aVR (TWAaVR) were found to be independently

associated with CS, with TWAaVR having a specificity of 89-97% [44].

Despite its advantages, as an inexpensive, non-invasive readily available test, ECG has a

relatively low sensitivity when it comes to diagnosis of CS. In patients with known sarcoidosis

however, clinical evidence of ECG changes should warrant further evaluation to confirm or

exclude cardiac involvement.

Exercise ECG

The role of exercise ECG is unclear, largely due to the lack of data in this field. A variety of non-

specific repolarization changes have been observed on exercise ECG tests in a cohort of 84

sarcoidosis proven patients [45]. Other investigators tested ECG’s and exercise stress tests on

35 patients with known stable pulmonary sarcoidosis confirmed by normal pulmonary function

tests. Over 50% of these patients complained of exertional dyspnea and had inappropriately

high heart rate responses to exercise. These findings suggested that impaired cardiac rather

than pulmonary function was the major limitation of exercise, indicating possible subclinical

cardiac involvement in these patients [46].

15
Holter Monitoring

Twenty-four hour Holter monitoring had been studied in order to identify arrhythmias and

conduction disturbances in asymptomatic patients with CS. In a Japanese prospective study of

38 patients with known extracardiac sarcoidosis, those who were later diagnosed with CS have

been noted to have more than 100 ventricular ectopic beats in a 24-hour period. They

concluded that Holter monitoring had 67% sensitivity and 80% specificity for arrhythmias in this

population [47]. Unfortunately, very few nonrandomized studies have been done in regards to

this modality and clinical application of these findings is uncertain.

Echocardiography

Two-dimensional echocardiography can often be a useful noninvasive method to assess

anatomical and functional changes of the myocardium. Echocardiography has been reported to

show pathological findings in up to 77% of patients with systemic sarcoidosis (48, 49). Current

recommendations include echocardiography as an initial study in the evaluation of patients

with suspected or known CS involvement [39, 40].

16
CS echocardiographic findings may vary, and include global or focal wall motion abnormalities

(hypokinesia/dyskinesia), chamber enlargement, ventricular wall thinning, dilatation or

hypertrophy (Figure 2), reduced ejection fraction, diastolic dysfunction, valvular regurgitation,

papillary muscle dysfunction, and aneurysmal dilations of ventricular chambers [50]. Two-

dimensional echocardiograms may demonstrate macroscopic areas of bright echoes, reflecting

granulomatous inflammation and exhibiting a “speckled” or “snowstorm” pattern [51, 52].

Cycle dependent variation of myocardial integrated backscatter (CV-IB) and pulmonary capillary

contrast assessment have also been studied in attempts to increase sensitivity of

echocardiography in screening sarcoidosis patients [53]. Thinning or thickening of the left

ventricular wall, usually the septum, has been noted to be prevalent in Japanese studies [54].

Regional wall motion abnormalities preferentially affected the anterior and apical portions of

the left ventricle in CS [54, 55]. Diastolic dysfunction has been reported in nearly 50% of

patients from the small study of CS [56], but whether diastolic dysfunction is specific remains

unknown. Newer techniques, including strain rates, are promising for greater sensitivity and

earlier diagnosis [57]. In addition, the use of speckle-tracking had demonstrated the ability to

detect decreased longitudinal left ventricular strain earlier and was statistically significant in

association with adverse clinical outcomes [58, 59].

17
Echocardiography remains a useful imaging tool and should be readily used as initial screening

tool in patients with suspected CS. Although echocardiography alone is not sufficiently

sensitive to detect early myocardial sarcoid lesions, in conjunction with other tests, it can

provide essential information in the diagnosis and progression of the disease. Use of

echocardiography to monitor for disease progression has been generally accepted due to its

availability, lack of radiation exposure, and ability to rapidly detect structural and functional

changes.

Radionuclide Imaging

201-Thallium (201Th)

201
Myocardial Th imaging has been most frequently and thoroughly studied in patients with

suspected CS. Thallium scans have demonstrated left ventricular perfusion defects, and some

have shown abnormal right ventricular uptakes [31, 50]. Some studies have reported perfusion

defect detection rates of approximately 30% [50, 60].

18
 201
Researchers have hypothesized that perfusion defects seen on Th scans are consistent with

granulomatous process since they do not follow the coronary artery anatomy patterns [61].

Hence, in the presence of normal coronary studies, defects on thallium imaging are suggestive

of a myocardial process [61]. Some authors had proposed that microvascular vasoconstriction

may be the pathogenic mechanism of these perfusion defects. This is supported by reversibility

of perfusion defects between post-injection rest and delayed images [62].

The relationship between the abnormal thallium perfusion defects and clinical cardiac

dysfunction has not been elucidated and evidence is lacking in this field. Thus, in the absence of

cardiac symptoms or signs suggestive of sarcoid involvement, thallium scans are generally not

recommended as a routine screening tool for cardiac sarcoidosis.

99-Technetium (99Tc) and 67-Gallium (67Ga)

99 67
While Tc and Ga scans have higher specificity for myocardial sarcoid, their sensitivity is

lower compared to thallium based scans. Patients with positive gallium scans almost always

have perfusion defects on thallium imaging [19, 32, 63]. Interestingly, two Japanese studies
67
noted that corticosteroid therapy was effective only in patients with a positive Ga scan,

suggesting that 67Ga scanning may have prognostic value [64-65], however, this relationship has
67
not been validated in other reports. As mentioned previously, while Ga imaging has been a
19
part of the modified diagnostic criteria in JMHW guidelines, it is no longer used by most centers

due to its low sensitivity. Gallium based scans have been demonstrated to be inferior in their

sensitivity and diagnostic accuracy in comparison with 18F-FDG PET [66]. With regards to 99Tc,

just like 201Th, abnormal 99Tc scans are not diagnostic of CS and their clinical significance has not

been established [67].

Positron Emission Tomography Imaging

Positron Emission Tomography (PET) has emerged as a superior diagnostic technique, as it

provides improved sensitivity and spatial resolution over other types of radionuclide imaging

[68]. 18F-FDG (18F-fluoro-2-deoxyglucose) PET imaging is a useful tool for the early diagnosis

and assessment of CS. Several studies have shown increased sensitivity of 18F-FDG imaging

over 67Ga, 201Th, and 99Tc imaging for the diagnosis of CS [69, 70]. A recent meta-analysis of 7

studies reported a range of sensitivities of 79-100% and specificities of 38-100% [71]. However,

comparison of the diagnostic accuracy of 18F-FDG PET with CMR has been limited. To date, only

one small study compared the diagnostic accuracy of 18F-FDG PET with CMR on 8 patients

positive by JMHW criteria and had concluded that PET may have a higher sensitivity, although

this conclusion was based on only 8 patients and hence the results were not statistically

significant [72] limiting their application.

20
A retrospective analysis of patients with CS and implantable cardioverter-defibrillators (ICDs) by

Betensky and colleagues, showed a significant relationship between the presence of active

myocardial inflammation on PET imaging and risk of ventricular arrhythmias, regardless of their

ejection fraction [73]. A larger retrospective study of 118 patients found that the presence of a

perfusion defect and increased 18F-FDG uptake was associated with an increased risk of death

or ventricular arrhythmia, even after adjusting for ejection fraction, the presence of

extracardiac sarcoidosis, and the JMHW clinical criteria. The same study also showed increased

risk for cardiac events in those with focal right ventricular uptakes of 18F-FDG [36].

Measurement of cardiac metabolic activity using FDG PET has also been entertained and found

it to be independently associated with adverse events [74], albeit, more research is needed to

fully understand the role of 18F-FDG PET imaging in the diagnosis and prognosis of patients

with CS [8].

Recent studies have also proposed novel tracers that may be more specific in binding

inflammatory cells in these patients. Both 68-Ga-DOTA-NaI-octreotide (a somatostatin

analogue) and 18F-fluoromisonidazole were reported to have increased uptakes in

granulomatous cells. More research is underway to further investigate the potential benefits of

these novel agents [37, 75].

21
Cardiac Magnetic Resonance Imaging

In the recent years, cardiac magnetic resonance imaging (CMR) has become very promising in

early detection of CS. Its accuracy and resolution are able to capture subtle structural and

functional abnormalities, which can be used to differentiate them from ischemic lesions. That

and lack of radioactivity make it a well-suited method for screening/diagnosing CS.

CMR imaging offers a specificity of around 78% [37]. It is able to detect a large spectrum of

myocardial changes in CS patients, from granulomatous infiltration including inflammation to

reactive edema, fibrosis, assessment of ventricular function and perfusion defects and rarely

microvascular vasculitis [8, 9, 125]. Presence of late gadolinium enhancement (LGE) is both a

pathognomonic and diagnostic finding on CMR, suggestive of a fibrotic process. LGE is based on

the principle of a delayed gadolinium washout period from areas of scarring, which allows it to

identify very small areas of fibrosis [76]. Many different patterns of gadolinium enhancement

can be seen in patients with CS (Figure 3). The most common patterns include subepicardial

and midwall enhancement of the basal septum or inferolateral wall [77], but right ventricular

abnormalities may also be seen [8]. Sole presence of LGE has been demonstrated to be more

sensitive than the JMHW criteria in a study of 58 patients with extracardiac sarcoid from
22
Netherlands [37].

CMR with LGE has been included in the 2014 HRS consensus algorithm in both evaluation of

patients with biopsy proven extracardiac sarcoidosis, as well as screening of individuals <60

years of age who present with an unexplained Mobitz II or third degree heart block [40]. A

study of 81 patients with known sarcoidosis had demonstrated that the presence of scar on LGE

imaging was twice as sensitive as the JMHW criteria to detect cardiac involvement, and LGE was

associated with a nine-fold increase in death, defibrillator discharge, or eventual need for

pacemaker [35]. This relationship was further reinforced in a large meta-analysis by Coleman

and colleagues [78]. More recent studies have demonstrated the presence of myocardial

scarring to be an independent risk factor for death, ICD therapy, and ventricular arrhythmias

[79]. T-2 weighted sequence myocardial edema as well as dynamic and structural ventricular

changes on CMR may also be suggestive of cardiac sarcoid involvement [8, 80, 81]. Among

patients with known CS and complete heart block, T-2 weighted sequences (compared with

FDG-PET uptake) demonstrated areas of myocardial inflammation responsible for heart block

[71, 82]. Dynamic, structural and functional changes of right ventricle have also been evaluated

by CMR and may correlate with either pulmonary involvement (pulmonary hypertension) or

direct myocardial infiltration [8]. Clinical importance of these findings has been supported by an

23
autopsy study by Roberts and colleagues, who found a direct relationship between right

ventricular granulomatous infiltration and presence of arrhythmias, conduction disturbances,

and heart failure in patients with known CS prior to death [15]. Another recent study by

Crawford and colleagues had also demonstrated through CMR that patients with evidence of CS

are at increased risk of ventricular arrhythmias (VT/VF), despite preserved ejection fractions. In

addition, right ventricular delayed enhancement was associated with increased rates of

ventricular arrhythmias especially in those with prior history of arrhythmias. Interestingly, sole

presence of delayed enhancement was not associated with adverse outcomes as previously

established by Patel and colleagues [83]. Due to its high sensitivity in the detection of fibrosis,

CMR late gadolinium enhancement has also been implemented in identifying these areas as

targets for EMB and had resulted in significant improvement in biopsy success rates [84].

Future research is targeting diagnostic and therapeutic utilities of T1 or T2-mapping techniques

in CS [81]. Although CMR and FDG-PET were not sufficiently compared head-to-head, this

paved the way for hybrid, imaging which combines both imaging modalities and is currently

being investigated [85].

24
Coronary Angiography

Coronary angiograms are often performed in patients with suspected CS to exclude coronary

artery disease. Given that CS cardiomyopathy is categorized as a non-ischemic type, majority of

patients will have normal angiographic studies. However, in advanced disease, CS may manifest

as a form of vasculitis, with macrovascular lesions visualized during coronary angiography [19,

126].

Endomyocardial Biopsy

Previous practice emphasized on tissue biopsy for diagnosis. In patients with extracardiac

disease, biopsy of lymph nodes and other more accessible organs (skin, lungs, liver, and

kidneys) is targeted first, mainly due to the higher diagnostic yield and lower procedural

complication rates. In cases of suspected isolated cardiac involvement, EMB is often required

with any attempt to confirm the diagnosis [27].

Endomyocardial biopsies were first introduced in 1962. They are nearly always taken from the

right ventricle, which makes CS diagnosis somewhat challenging as sarcoid granulomas have a

variable distribution in the myocardium and tend to involve the interventricular septum and left

ventricle. The general reported success rate is less than 25% [86-88], but implementation of

electrophysiological (EP) mapping and image guided (PET/CMR) techniques has improved

positive biopsy rates up to 50% [30, 89]. Both European and American guidelines encourage use
25
of supplementary imaging guidance when considering endomyocardial biopsy [40, 90].

E. Clinical Management

Treatment of CS is aimed at controlling inflammation, preventing fibrosis and preserving cardiac

structure and function. Therapy is similar to those of heart failure patients. Nevertheless, CS

management is challenging as many patients have clinically silent disease in contrast to those

who present in decompensated heart failure and require aggressive therapy. The main

therapeutic approaches can be broadly divided into two categories: pharmacological and

invasive or device-oriented. Pharmacological management consists of corticosteroid and other

various immunosuppressive regimens, in addition to the standard heart failure therapy.

Invasive management includes ablation of ventricular arrhythmic foci, pacemaker/implantable

defibrillator placement and heart transplantation.

Immunosuppressive Therapy

Glucocorticoids have been a well-known therapeutic choice when it comes to sarcoidosis. Their

hypothesized therapeutic mechanism is the ability to attenuate both inflammatory response

from granulomatous infiltration and to halt the progression of fibrosis. Benefit of

corticosteroids in CS has been extrapolated from non-cardiac sarcoidosis research. There is a

26
paucity of data in regards to their implication in treatment of CS. No randomized controlled

trials evaluating prednisone for treatment of CS have been completed. Anecdotal data from an

observational survey-based study of 104 cases demonstrated increased survival [91]. In another

retrospective observational study from Japan, a 75% survival at 5 years in the glucocorticoid

arm versus 10% in non-steroid treated patients was noted. In those with left ventricular

ejection fraction of >50% prior to treatment initiation, the 10 year survival increased to 89%.

The optimal dose of prednisone and duration of therapy has not been established. Japanese

authors have suggested that an initial dose as low as 40 mg per day may be effective, followed

by a slow taper over 6-12 months once symptomatic improvement has been achieved [25].

Survival curves were actually similar in high (40 mg) prednisone versus low (<30 mg) prednisone

groups. Other data does suggest that treatment with prednisone is effective in preventing

progressive heart failure, scar formation, and sudden death [91, 92]. Unfortunately, CS may

progress despite aggressive corticosteroid treatment [93]. Data from current studies points

towards the benefit of early initiation of corticosteroid treatment in patients with suspected

cardiac involvement. Although evidence regarding medical therapy is lacking, proposed

regimens include 1 mg/kg/day prednisone for 4 weeks or an initial high dose of at least 40 mg

with a gradual taper thereafter [41]. Serial FDG-PET scans have been used to monitor steroid

therapy in patients with active cardiac involvement. Increased uptake on scan after steroid

therapy was associated with poor clinical outcome, which may help identify steroid-resistant
27
sarcoidosis earlier [94]. Nevertheless, prompt initiation of corticosteroid therapy is vital as it

may improve outcomes, decrease ventricular arrhythmias and even lead to a complete

recovery of atrioventricular conduction [95, 96].

Immunosuppressive therapy including with cyclophosphamide, infliximab, azathioprine,

rituximab and methotrexate have also been tried, but their outcomes have not been supported

by randomized controlled trials [22, 97-99]. Combination therapy with corticosteroids and

immunosuppressive agents has also been reported, but the data is largely anecdotal, based on

case reports and extrapolated from non-cardiac sarcoidosis cases [100]. Medical treatment of

CS remains a challenge. Future studies are needed to help develop a standard medical

approach to treatment. Given the variable presentations of the disease however, therapy may

need to be individually tailored more so than other cardiac diseases. Presence of extracardiac

manifestations of sarcoidosis also needs to be taken in consideration while determining the

ideal regimen of immunosuppression and duration of therapy.

28
Heart Failure

In addition to trials of corticosteroid therapy, management of heart failure symptoms in these

patients follows the same current recommendations as for patients with heart failure

attributed to ischemic or other causes of non-ischemic cardiomyopathy.

Goals include preservation and maintenance of left ventricular function, as well as prevention

of cardiac related death. Institution of guideline recommended medical and device based heart

failure therapy are the cornerstones of treatment. Medical therapy includes ACE-inhibitors or

angiotensin receptor blockers (ARBs), beta-blockers, diuretics and mineralocorticoid receptors

antagonists. Device therapy includes placement of implantable cardiac defibrillator (ICD) for

primary or secondary prevention of sudden cardiac death, and cardiac resynchronization

therapy (CRT) in appropriate patients.

CS and non-CS associated heart failure may have different responses to standard heart failure

therapy however. This is evidenced by recent small study, which compared outcomes of CRT in

CS patients with a group of patients with dilated cardiomyopathy attributed to other causes

and found sarcoidosis patients to have higher mortality rates despite CRT therapy [101].

29
Heart Transplantation

Heart transplantation should be considered for patients with severe intractable heart failure

symptoms that are refractory of maximum tolerated goal directed medical therapy according to

the current guideline recommendations. Favorable post-transplant outcomes with survival of

92% at one year and 83% at five years have been reported [102]. Survival was similar to

patients that underwent heart transplantation for an alternate diagnosis. Data on recurrence of

CS has been mixed. Some studies of allograft recipients [103-105] did not identify recurrence of

disease, while other authors reported recurrence [106, 107]. Nevertheless, the number of

transplant recipients studied to date has been rather small and hopefully as the awareness of

CS continues to increase, more data on rates of transplant success or failure will surface.

Management of Conduction Abnormalities

Conduction abnormalities are often the first presentation of cardiac involvement in sarcoidosis.

The latter is due to predilection for the involvement of the basal septum. Current consensus

recommends pacemaker implantation (Class IIa recommendation), largely because the

reversibility of heart block with immunosuppressive treatment in unpredictable and has not

30
been well studied. Since immunosuppression may increase the risk of device infection, HRS

consensus recommends device implantation prior to initiation of medical therapy [40].

Antiarrhythmic Management

Atrial arrhythmias

While true prevalence remains unknown, recent observational studies have reported a

substantial prevalence of atrial arrhythmias in CS patients [108]. It is believed that atrial

arrhythmias are likely secondary manifestations of atrial myocardial inflammation and scarring.

Progressive left atrial enlargement as a result left ventricular dysfunction may also be a

contributing factor [109]. Viles-Gonzalez and colleagues, in a study of 100 biopsy proven

extracardiac sarcoidosis patients have detected a 32% prevalence of supraventricular

arrhythmias, of which atrial fibrillation was 18% [110]. In patients with atrial fibrillation, general

thromboprophylaxis guidelines for treatment of non-valvular atrial fibrillation should be applied

since no current data supports that CS patients are at a higher risk of thromboembolic events

[40, 111]. Antiarrhythmic therapy is similar to contemporary management of atrial fibrillation

of other etiologies. It is generally comprised of rate control (beta-blockers, calcium-channel

blockers) and rhythm control (ie. Sotalol, Dofetilide and Amiodarone) strategies. The role of

electrophysiological studies is unclear, but could be considered on individual basis [40, 112].
31
Ventricular arrhythmias

Sarcoidosis patients have increased predisposition for ventricular arrhythmias confirmed by 10-

year follow up prospective study [113]. Ventricular arrhythmias more commonly follow a

macro-re-entrant pathway in the area of granulomatous infiltration [114, 115] but non-

reentrant mechanism ventricular arrhythmias have also been described [91, 116]. The role of

immunosuppressive therapy in these patients in controversial, several studies [115-117] have

demonstrated benefit while others [118, 119] demonstrated worsening pro-arrhythmic

component with steroid therapy. For these reasons antiarrhythmic drug therapy remains a

cornerstone. Amiodarone is the drug of choice, but should be used with caution as CS patients

often experience both bradyarrhythmias and tachyarrhythmias. Amiodarone has well known AV

nodal blocking properties, which could exacerbate pathologic bradycardias [127]. In addition,

due to the potential for toxicities involving nearly every organ system, including potentially fatal

pulmonary side effects, close clinical monitoring of patients on amiodarone is essential [128].

Electrophysiological studies have been used with attempts to locate arrhythmogenic foci

especially in patients who had failed initial immunosuppressive therapy [115]. Common sites of

involvement were identified to be para-tricuspid area and right ventricular apex [120]. CMR

with LGE supplementation has been used to locate scars for targeted ablation [121]. Success of

32
radiofrequency ablation (RFA) therapy has diversified reports; some studies [115, 122, 123]

demonstrated favorable outcomes, whereas another study reported recurrence of ventricular

arrhythmias [124] despite successful initial RFA.

ICD implantation

There is limited data regarding ICD benefit in this patient population. Current recommendation

(Class IIa recommendation) urges ICD implantation (Table 4) in patients with known CS and

spontaneous sustained ventricular arrhythmias, including prior cardiac arrest, and/or if left

ventricular ejection fraction is <35% despite optimal medical therapy and trial of

immunosuppression. ICD implantation can also be useful in patients with unexplained syncope

and inducible ventricular arrhythmias. ICD implantation has also been considered at the time of

pacemaker implantation (in those that meet criteria for pacemaker) or if patients have

evidence of late gadolinium enhancement on CMR [40].

Conclusion

Our knowledge about CS has amplified significantly over the last 30 years. The prevalence and

extent of cardiac involvement in sarcoidosis population is greater than previously thought. It

should be noted that a large amount of literature emanates from Japan, probably due to the

33
high prevalence of heart involvement in that population, but it does introduce a publication

bias on the subject that may not be entirely applicable to the American or European

populations. Nevertheless, the expanding global awareness about CS is largely attributed to the

development of new imaging techniques and modalities. The growing realization that cardiac

involvement is often asymptomatic is paving the way for better screening protocols and earlier

detection of this serious condition. There remains an uncomfortable lack of hard clinical data on

what is the best treatment approach to this patient population. Guidelines are in the process of

being written and updated. It seems very likely that we have only uncovered the tip of the

iceberg when it comes to our understanding of this disease.

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Figure Legend

Figures

Figure 1. Number of publications per year using the keyword search “cardiac sarcoidosis” in

PubMed database

Figure 2. Echocardiogram. Two-dimensional apical four chamber view (chambers labeled)

demonstrating prominent biventricular dilation, interventricular as well as left ventricular wall

thinning in a patient with cardiac sarcoidosis.

*RA- Right atrium, LA - Left Atrium, RV - Right ventricle, LV - Left ventricle

Figure 3. Cardiac MRI. Delayed enhancement of interventricular septum (white arrows) in a

patient with known extracardiac sarcoidosis and non-ischemic cardiomyopathy.

*RV - right ventricle, LV - left ventricle

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Tables

Table 1. Japanese Ministry of Health and Welfare criteria for diagnosis of CS (2006).

Table 2. Heart Rhythm Society (HRS) consensus statement for diagnosis of cardiac sarcoidosis.

Table 3. Heart Rhythm Society (HRS) consensus statement on screening for cardiac

involvement.

Table 4. Heart Rhythm Society (HRS) consensus statement on ICD implantation in patients with

cardiac sarcoidosis.

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Table 1.

Histological Diagnosis

1. Cardiac Sarcoidosis confirmed with positive EMB specimens demonstrating non-caseating

epithelioid granulomas with histological or clinical diagnosis of extracardiac sarcoidosis

Clinical Diagnosis

1. EMB does not demonstrate noncaseating epithelioid granulomas with histological or clinical

diagnosis of extracardiac sarcoidosis and satisfies:

͑͑͑͑͑͑A. ≥ 2/4 major criteria

B. 1/4 major criteria + ≥ 2/5 minor criteria

Major criteria:

1. Advanced AV block

2. Basal thinning of the interventricular septum

3. Positive Gallium-67 cardiac uptake

4. Depressed LVEF of <50%

Minor criteria:

1. Abnormal ECG findings (ventricular arrhythmias, complete RBBB, axis deviation,

abnormal Q-waves)

2. Abnormal echocardiogram (wall motion abnormality, morphological abnormality such as an

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 aneurysm, wall thickening or ventricular dilation)

3. Perfusion defects on nuclear imaging (Thallium-201, Technetium-99m SPECT)

4. Delayed gadolinium enhancement on CMR

5. Interstitial fibrosis or monocyte infiltration on EMB

Adapted from (8)

*EMB - endomyocardial biopsy, AV - atrioventricular, LVEF - left ventricular ejection fraction,

ECG - electrocardiogram, RBBB - right bundle branch block, CMR - cardiac magnetic
resonance imaging.

Table 2.

Histological Diagnosis

1. EMB specimens with non-caseating epithelioid granulomas

2. No alternative cause of non-caseating epithelioid granulomas identified

Clinical Diagnosis

1. Histological diagnosis of extracardiac sarcoidosis

2. Alternative cardiac causes have been excluded

3. One or more of the criteria below

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Criteria

1. Corticosteroid or immunosuppressive therapy responsive cardiomyopathy or heart block

2. Unexplained reduced LVEF <40% or depressed LVEF <50%

3. Mobitz type II second degree heart block or third degree heart block

4. Patchy cardiac uptake on FDG-PET in a pattern consistent with cardiac sarcoidosis

5. Late gadolinium enhancement on CMR in a pattern consistent with cardiac sarcoidosis

6. Positive Gallium-67 uptake in a pattern consistent with cardiac sarcoidosis

Adapted from (27, 40)

* EMB - endomyocardial biopsy, LVEF - left ventricular ejection fraction, FDG-PET -

fluorodeoxyglucose positron emission tomography, CMR - cardiac magnetic resonance imaging

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Table 3
Class I

1. Patients should be asked about unexplained syncope, pre-syncope or palpitations (lasting >2

weeks)

2. Patients should be screened with 12-lead electrocardiogram

Class IIa

1. Advanced cardiac imaging (CMR or FDG-PET) can be useful in patients with one or

more abnormalities detected on initial screening by symptoms, electrocardiogram and

echocardiogram

Class III

1. Advanced cardiac imaging (CMR or FDG-PET) is not recommended for patients without

abnormalities on initial screening

Adopted from (40)

*CMR - cardiac magnetic resonance imaging, FDG-PET - fluorodeoxyglucose positron emission

tomography

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Table 4.

Class I (ICD implantation is recommended)

1. Spontaneous sustained ventricular arrhythmia, including prior cardiac arrest

2. LVEF ≤35% despite optimal medical therapy and a trial of immunosuppression (in

presence of active inflammation)

Class IIa (ICD implantation can be useful)

1. Patient meets an indication for permanent pacemaker implantation

2. Unexplained syncope or near-syncope felt to be arrhythmic in etiology

3. Inducible sustained ventricular arrhythmias (>30 seconds of monomorphic/polymorphic

VT) or clinically relevant VF

4. ICD should be implanted if the patient undergoes VT ablation

Class IIb (ICD implantation may be considered)

1. Patients with LVEF 36-49% and/or an RV ejection fraction of ≤40% despite optimal

medical therapy and a trial of immunosuppression (in presence of active inflammation)

Class III (ICD implantation is not recommended)

1. Patients with no prior history of syncope, those that have a normal LVEF/RVEF, no LGE

on CMR, a negative EP study, and no indication for permanent pacemaker‫ܚ‬

2. Presence of incessant ventricular arrhythmias

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3. Severe NYHAclass IV heart failure

‫ܚ‬
These patients should be followed clinically to monitor for deterioration of ventricular function

Adopted from (40)

*LVEF - left ventricular ejection fraction, RVEF - right ventricular ejection fraction, VT -
ventricular tachycardia, VF - ventricular fibrillation, ICD - implantable cardioverter defibrillator,
RV - right ventricle, LGE - late gadolinium enhancement, CMR - cardiac magnetic resonance
imaging, EP study - electrophysiology study, NYHA - New York Heart Association

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