Journal of Cardiology 77 (2021) 154–159

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Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Review

The ECG in sarcoidosis – a marker of cardiac involvement?

Current evidence and clinical implications
Kevin Willy (MD)*, Dirk G. Dechering (MD), Florian Reinke (MD), Nils Bögeholz (MD),
Gerrit Frommeyer (MD), Lars Eckardt (MD)
Department for Cardiology II: Electrophysiology, University Hospital Münster, Münster, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by noncaseating
Received 18 April 2020 granulomas. Cardiac involvement is often limiting patients’ prognosis. Cardiac sarcoidosis can manifest
Received in revised form 30 May 2020 with variant cardiac arrhythmias, of which atrioventricular (AV)-block-related bradycardia and
Accepted 16 June 2020
ventricular tachycardias are the most common. Although cardiac sarcoidosis remains a histopathological
Available online 8 September 2020
diagnosis, the significance of imaging modalities, especially cardiac magnetic resonance imaging is
increasing rapidly but mainly remains reserved for patients with a high suspicion due to a previous
Keywords:
arrhythmia or unknown cardiomyopathy. Thus, there is a need for screening in daily clinical practice so
ECG
Sarcoidosis
that possible characteristic electrocardiographic (ECG) findings may guide the way to detect the disease.
Cardiac sarcoidosis We therefore evaluated the ECG as a potential tool for screening of cardiac sarcoidosis and present
Inflammatory heart disease different electrophysiological manifestations of cardiac sarcoidosis based on a literature review.
Ventricular tachycardia The ECG is a valuable tool for screening of cardiac involvement in patients with sarcoidosis. Several
QRS fragmentation parameters have been shown to be associated with cardiac involvement in sarcoidosis such as higher-
T-Wave abnormalities degree AV-block, QRS complex fragmentation and widening, as well as certain T wave abnormalities that
may indicate cardiac involvement, of which the latter two are most promising and specific. However,
prospective studies examining a large number of trials are desirable.
© 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Contents

AV conduction disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

The QRS complex in sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
The QT interval and T-wave characteristics in sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Atrial tachyarrhythmias in sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Ventricular tachyarrhythmias in sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

Introduction differences are documented. A U.S. registry revealed that lifetime risk
of sarcoidosis is around 0.85% for white Americans and 2.4% for
Sarcoidosis is a systemic granulomatous disease of still not people of African-American origin [1]. Apart from that, there is a
sufficiently understood etiology. Bilateral hilar lymphadenopathy is gradient from a high incidence in northern Europe gradually
the most frequent clinical manifestation. Geographical and ethnical declining to southern European countries. Cardiac involvement of
sarcoidosis (CS) varies in different geographical regions. In autopsy
studies it has been shown that 20% of Caucasians and black
* Corresponding author at: Universitätsklinikum Münster, Klinik für Kardiologie Americans and about 70–80% of Japanese patients [2,3] with
II: Rhythmologie, Albert-Schweitzer-Campus 1 Gebäude A1, D-48149 Münster, sarcoidosis had (subclinical) cardiac manifestations. Sarcoidosis
Germany. itself may be considered a benign disease in most cases because
E-mail address: kevin.willy@ukmuenster.de (K. Willy).

https://doi.org/10.1016/j.jjcc.2020.07.006
0914-5087/© 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
 K. Willy et al. / Journal of Cardiology 77 (2021) 154–159
spontaneous remission is often observed in extracardiac cases such
as skin and also pulmonary sarcoidosis. While clinical presentation is
often not specific, there are several diagnostic tools, which should be
combined to confirm the diagnosis. Diagnostic tools reach from
laboratory findings such as elevated levels of angiotensin-converting
enzyme (ACE), lysozyme, and soluble interleukin-2 (sIL2) receptor to
imaging modalities such as chest X-ray or computed tomography
(CT) and also more invasive strategies such as bronchoalveolar lavage
fluid analysis and histology extraction and analysis [4,5].
However, when cardiac involvement exists, outcome is
unfavorable due to granulomatous infiltration of ventricular
myocardium. Yazaki et al. reported that CS is associated with a
grim prognosis if left untreated with immunosuppressive agents
and underlined that outcome was worse compared to dilated
cardiomyopathy [6]. Because of that, CS may be responsible for as
much as 85% of deaths from sarcoidosis [7]. Fortunately, prognosis
has improved due to better diagnosis finding and treatment
options [8].
In patients with CS, various types of arrhythmias have been
reported. Among them, bradycardia from various degrees of
atrioventricular block (AVB) is the most common and ventricular
tachyarrhythmias (VT)/ventricular fibrillation (VF) are the second
most common initial presentation [9,10]. Roberts et al. [11]
reported that sudden cardiac death (SCD) due to VT/VF or AVB
and related complications account for 30–65% of deaths in
sarcoidosis. Nordenswan et al. [12] also showed that outcome of
CS is unfavorable in CS patients presenting with VT or AVB and that
risk for SCD was high in these patients during a 5-year-follow-up.
Therefore, detecting cardiac involvement and an early diagnosis
with treatment is one of the most important issues, especially
because immunosuppressive treatment substantially enhances
prognosis in such patients. AVB results from infiltration of the
intraventricular septum due to sarcoid granuloma or – at a later
stage – scar tissue. As sarcoidosis is typically a disease of middle-
aged persons and predominantly women, clinical suspicion of CS
should be high in middle-aged with “idiopathic” higher degree AVB
[13]. This is potentially of therapeutic interest, as several reports
suggest that AVB can recover after corticosteroid therapy [14,15]
indicating that AVB in CS may at least initially be related to the
active phase of this disease. On the other hand, VT in CS mainly
occur as scar related re-entrant mechanism. While cardiac
magnetic resonance imaging (MRI) and other imaging modalities
such as fluorodeoxyglucose-positron emission tomography (PET)
scans and also echocardiography give important clues for diagnosis
of CS, screening procedures such as blood and urine testing for
biomarkers such as ACE and sIL2-receptor testing and urinary
calcium in daily clinical practice are also of eminent importance. In
particular, N-terminal prohormone B-type natriuretic peptide (NT-
pro-BNP) and troponin I have been shown to be associated with CS
and associated with fatal arrhythmia in this disease [16]. To
identify cardiac involvement, characteristic electrocardiographic
(ECG) findings would be helpful to detect patients at risk or already
suffering from this potentially dangerous cardiac disease. Howev-
er, it has to be stated, that all studies have shown, that a normal
ECG does not exclude CS, so that the ECG can help to make the
diagnosis but cannot exclude it.
AV conduction disorders
A very common manifestation of CS is first and high degree AVB
[10]. Japanese as well as international guidelines list higher-degree
AVB as a major criterion for cardiac manifestation of sarcoidosis,
meaning that an extracardiac histopathological proof of sarcoido-
sis plus a higher-degree AVB allows physicians to make the
diagnosis of CS [17,18]. Additional imaging modalities such as
155
echocardiography or cardiac MRI may further support the
diagnosis and help to estimate the level of cardiac involvement.
Several studies have shown that the outcome in patients with
high-degree AVB as the initial manifestation of CS was better than
in those with VT and/or heart failure symptoms. This is probably
due to the fact that steroid treatment is particularly effective in
these patients, making AVB reversible in about 50% (40–57%) of
patients [6,14,19–21], whereas AVB did not resolve spontaneously
in untreated patients [21]. Apart from that, a reduced ejection
fraction or recurrent VT in CS might be a marker of more
pronounced cardiac involvement of sarcoidosis.
The QRS complex in sarcoidosis
The QRS complex in sarcoidosis plays a very important role,
especially for identifying patients at risk for cardiac involvement.
Schuller et al. [22] showed that in patients with pulmonary
sarcoidosis, a fragmented QRS complex as well as bundle brunch
block were associated with cardiac involvement. These results are
supported by another small study on CS which showed a close
relation of late gadolinium enhancement in cardiac MRI with
fragmented QRS [23]. In addition, Sobue et al. [24] demonstrated
that QRS-based assessment of myocardial involvement and
adverse events is also valid in patients with CS. Besides, signal-
averaged ECG (SAECG) may also be a useful tool in CS. In 14 of 27 CS
patients and 11 of 61 subjects with sarcoidosis but without known
cardiac involvement SAECG was abnormal [25]. The specificity was
100% in patients with narrow QRS complex (<0.1 s) reflecting a
high negative predictive value. Another ECG feature reported in CS
patients are epsilon waves of the QRS complex which make
differentiation from arrhythmogenic right ventricular cardiomy-
opathy (ARVC) or other right ventricular cardiomyopathies very
difficult [26–28]. Khaji et al. [27] reported a patient with giant
epsilon waves in his ECG who was initially diagnosed with ARVC by
task force criteria but was later on diagnosed with CS in an
endomyocardial biopsy [27]. This could be confirmed in a larger
electrophysiological study by our group [29].
The QT interval and T-wave characteristics in sarcoidosis
There is only little known about repolarization abnormalities
and possible implications in CS. Kasapkara et al. [30] examined
110 patients (54 with CS, 56 healthy subjects) and compared the
different characteristics of the QT interval and T-waves in both
healthy and CS patients. There was no difference in QT duration
between the two groups, but the authors found increased QT
dispersion in the CS group.
The T-wave amplitude in lead aVR has been described to be
associated with adverse cardiac events in various cardiovascular
diseases [31,32]. A Japanese group examined 93 consecutive
patients with sarcoidosis regarding a potential cardiac involve-
ment analyzing the 12-lead-ECG at rest [33]. They found that
bundle branch block as well as T-wave amplitude in lead aVR were
independently associated with cardiac involvement. Combination
of these two parameters showed promising diagnostic yield for
cardiac involvement (sensitivity 94%, specificity 89%). Another
diagnostic tool showing comparably good results (sensitivity
85.7%, specificity 92.8%) was microvolt T-wave alternans in a study
of 35 sarcoidosis patients [34]. However, this method is more
difficult to establish in daily clinical practice and the results should
be regarded as preliminary due to the small sample size. Besides,
beat-to-beat changes in the shape of the T-wave were present in
6 of 7 patients with CS and only in 2 of 28 patients with sarcoidosis
without cardiac manifestation. Furthermore, it was shown that the
interval of T-peak to T-end (Tpe) was longer in patients with CS
156 K. Willy et al. / Journal of Cardiology 77 (2021) 154–159

compared to healthy individuals [30]. In addition to that, Tpe/QT
ratio was also prolonged in CS patients.
Atrial tachyarrhythmias in sarcoidosis
There are only few studies concerning the prevalence and
the importance of atrial arrhythmias in CS. Viles-Gonzalez et al.
[35] reported that supraventricular tachyarrhythmias are
present in 32 out of 100 patients with biopsy-proven
sarcoidosis. They performed close monitoring of these
100 patients who had no history of atrial arrhythmias at the
beginning of the observation period. In about one third (n = 9)
of these 32 patients atrial tachyarrhythmias could not be
controlled by drug treatment, so that ablation was performed.
In 7 patients the origin of the arrhythmia was in the left atrium
(5 atrial fibrillation, 2 left atrial flutter). Ablation could restore
and keep sinus rhythm in all of them. Thus, it was concluded
that atrial tachyarrhythmias can be treated safely and
effectively by catheter ablation [36].
A case report by Bhaskaran et al. [37] illustrated that atrial
inflammation in a CS patient led to sinus node dysfunction and
cavotricuspid isthmus-dependent atrial flutter and could under-
line that by different diagnostic modalities (MRI, PET-CT, HD-
mapping, and histopathological analysis). However, sinus node
dysfunction is not a common or typical occurrence in CS.
Nonetheless, especially if supraventricular arrhythmias are

Fig. 1. A 33-year-old female with cardiac sarcoidosis and sustained ventricular tachyarrhythmia (VT). Panel A shows the patient’s resting electrocardiogram (ECG) with T-wave
inversions in the inferolateral leads. Panel B shows left ventricular voltage MAP with red regions indicating low voltage areas with myocardial scar. Cardiac echo showed a
slightly reduced left ventricular ejection fraction with inferobasal hypokinesia framed in blue color (C). A 12-lead ECG shows the clinical VT (D) from the basal posterolateral
region which was successfully ablated.

Fig. 2. A 35-year-old athletic male initially presenting with a well-tolerated ventricular tachyarrhythmia (VT). After proof of sarcoidosis and steroid treatment, the same VT
could be induced with a faster rate one year later. Resting electrocardiogram with an atypical right bundle branch block and inverted T-waves plus epsilon waves in the right
precordial leads (A). In panel B, an inducible VT with a left bundle branch block/superior axis configuration and a cycle length of 400 ms prior to corticosteroid therapy is
shown. Panel C demonstrates the same inducible VT, but with accelerated cycle length of 240 ms after one year of steroid treatment. Low-voltage right ventricular scar areas
were detected in a 3D CARTO Map (D). Myocardial scar is displayed in red color, green and blue color representing the border zone between scar and electrically normal
myocardium in pink. Noncaseating granulomas with giant cells in a hematoxylin-eosin stain from a bronchial biopsy (E).
Table 1
Overview of studies analyzing different ECG parameters in sarcoidosis patients with and without cardiac involvement.

ECG parameter Publication Number of patients Results Statistical measures

Fragmented QRS Homsi, 2009 [23] 17 with extracardiac sarcoidosis fQRS was associated with later Specificity 80%
diagnosis of CS (p = 0.002) Sensitivity 100%
PPV 78%
fQRS was more often in pts with CS NPV 100%
Tanaka, 2016 [33] 93 with sarcoidosis (26 with CS) (p < 0.01)
OR 2.29 (CI 0.26
19.7)
Prolonged QRS Dechering, 2013 [29] 18 with CS or ARVC (8 with CS) CS pts had a wider QRS complex n.a.
(p < 0.04)

Tanaka, 2016 [33] 93 with sarcoidosis (26 with CS) CS pts had a wider QRS complex
(p < 0.01) n.a.

K. Willy et al. / Journal of Cardiology 77 (2021) 154–159

Tanaka, 2016 [33] BBB was associated with CS
Bundle branch block (p < 0.01)
Specificity 97%
Sensitivity 61%
OR 235.5 (CI 27.4
4928)
QTc dispersion Kasapkara, 2017 [30] 110 (54 with sarcoidosis, 56 healthy) QTc dispersion was longer in the n.a.
sarcoidosis group (p < 0.001)
Tpeak-Tend interval Kasapkara, 2017 [30] 110 (54 with sarcoidosis, 56 healthy) Interval was longer in the n.a.
sarcoidosis group (p < 0.001)
Signal-averaged ECG Schuller, 2011 [25] 88 with sarcoidosis and suspected CS SAECG was abnormal in more Specificity overall 82%
patients with CS than in those Sensitivity overall 52%
without (p < 0.01) PPV 0.56
NPV 0.79
In pts with QRS < 100 ms SAECG
had an optimized specificity
In pts with narrow QRS (<100 ms):
Specificity 100%
Sensitivity 36.8%
T-wave alternans Matsumoto, 2009 [34] 35 with sarcoidosis (7 with CS) T-wave alternans appears more Specificity 92.8%
often in pts with CS Sensitivity 85.7%
PPV 75%
NPV 96.3%
T-wave amplitude in lead aVR Tanaka, 2016 [33] 93 with sarcoidosis (26 with CS) T-wave amplitude in aVR is higher Specificity 92%
in pts with cardiac involvement Sensitivity 39%
(p < 0.01) OR 5.75 (CI 1.98
22.8)
T-wave inversion Tanaka, 2016 [33] 93 with sarcoidosis (26 with CS) T-wave inversion was associated n.a.
with cardiac involvement (p < 0.01)
BBB, bundle branch block; CS, cardiac sarcoidosis; CI, confidence interval; fQRS, fragmented QRS; NPV, negative predictive value; n.a., not available; OR, odds ratio; pts, patients; PPV, positive predictive value.

157
158 K. Willy et al. / Journal of Cardiology 77 (2021) 154–159
suspected, Holter-ECG as well as use of implantable loop
recorders may be useful for more elaborate monitoring.
Ventricular tachyarrhythmias in sarcoidosis
VTs are a common initial manifestation of CS [10]. While AVB
shows a relatively favorable outcome, VT is associated with worse
prognosis. Banba et al. [14] reported that VT is an expression of
advanced disease stage and therefore associated with worse
outcome. This is in line with an analysis by Skowasch et al. [38]
testing the wearable cardioverter defibrillator (WCD) in CS patients
for primary prevention. In that study a high number of patients
(22%) were treated for VT/VF. Furthermore, it could be shown that
particularly patients with heart failure and a markedly reduced left
ventricular ejection fraction (LVEF) (LVEF of WCD group with shock
21% vs not-shocked 48%) developed VT in advanced stages of CS.
Fig. 1 illustrates the case of a 33-year-old woman with initially
unknown cardiomyopathy who was admitted for recurrent
implantable cardioverter defibrillator (ICD) shocks due to mono-
morphic VT. An electrophysiological study revealed pronounced
left ventricular low voltage areas while lung biopsy could prove the
suspected sarcoidosis. After steroid treatment, there was no
recurrence of VT for two years. Of note, the patient died under
unclear circumstances in her parked car. There were no
arrhythmias stored on her ICD to explain her death.
The underlying mechanism of VT occurrence is closely linked
to the level of inflammation in these patients. Ishiguchi et al.
could show that urinary 8-hydroxy-20 -deoxyguanosine as a
marker of oxidative stress was elevated in CS patients suffering
VT and could reliably predict VT occurrence in CS patients as an
independent determining factor. Furthermore, this protein
could also be found in myocardial biopsy samples indicating a
causal role [39].
In current European Society of Cardiology guidelines there is a
class IIb recommendation for early implantation of an ICD if CS
patients present with VT even in the absence of an adequate
immunosuppressive therapy. This recommendation is in contrast
to other inflammatory cardiomyopathies and underlines the high
risk for life-threatening VTs in CS [40]. Fig. 2 illustrates the case of a
35-year-old asymptomatic male competitive soccer player who
initially presented with a well-tolerated VT. He was diagnosed to
have biopsy proven CS. After one year of steroid therapy the same
but now much faster VT was inducible. Thus, therapy for acute
inflammation may accelerate conduction and thereby even act
proarrhythmically. Concerning the electrophysiological character-
istics of CS versus ARVC as a common differential diagnosis, our
group showed that VT more often originate from the apical right
ventricle and that programmed stimulation may provoke many
different monomorphic VT as compared to patients with ARVC
[29]. Of note, the presence of first or higher degree AVB may also
differentiate CS from ARVC. Although often multiple VT are
inducible in CS, ablation seems to be a promising option, resulting
in a significant reduction of arrhythmia burden [41]. Furthermore,
due to the high risk of various tachyarrhythmias, Birnie et al. [42]
stated that most patients with clinically manifest disease require
an ICD over time as disease severity and prognosis is mostly
determined by left ventricular involvement [43]. Screening for CS
seems important as a significant part of patients with VT and
previously unknown underlying heart disease are later diagnosed
with CS according to a prospective trial by Nery et al. [44], where
28% of patients with monomorphic VT and undefined cardiomy-
opathy were diagnosed with CS later on. In line with these results,
our group showed the value of 3D electroanatomic voltage
mapping to guide biopsy sampling in previously unexplained
cardiomyopathies [29].
Conclusion and clinical implications
Sarcoidosis is a histopathological diagnosis, cardiac involve-
ment is nowadays usually suggested by cardiac MRI. Komada et al.
[45] could reveal that late gadolinium enhancement can be found
in the left ventricle, especially in the basal septal wall in patients
with CS. MRI can also be used for risk stratification concerning VT
[46]. Convenient and simple screening methods have not yet been
established as the e.g. ECG has often been said to be unspecific and
imprecise. Nevertheless, ECG screening in patients with primarily
extracardiac sarcoidosis seems to be useful as there are several
potential ECG features as hints for CS (please also look at Table 1).
On the other hand, a normal ECG does not exclude CS but makes
severe cardiac involvement unlikely. Most data exist for anomalies
of AV conduction and the QRS complex. Fragmented QRS complex
as well as (atypical) bundle branch block are suspicious for cardiac
involvement in sarcoidosis patients. T-wave abnormalities have
also been repeatedly described to be helpful for screening in CS. In
patients with extracardiac sarcoidosis, ECG abnormalities should
therefore raise suspicion of CS. The most promising discriminatory
parameters are higher-degree AVB, increase and fragmentation of
QRS, as well as certain T wave abnormalities. Besides, patients with
no previously known heart disease presenting with high-grade
AVB should be carefully examined for CS, as underlying diagnosis
because treatment may have a major prognostic impact.
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