Circulation Journal

Circ J 2020; 84: 685 – 694

REVIEW
doi: 10.1253/circj.CJ-19-0705

Cardiac Arrhythmias in Autoimmune Diseases

Monika Gawałko, MD; Paweł Balsam, MD, PhD; Piotr Lodziński, MD, PhD;
Marcin Grabowski, MD, PhD; Bartosz Krzowski, MD;
Grzegorz Opolski, MD, PhD; Jędrzej Kosiuk, MD, PhD

Autoimmune diseases (ADs) affect approximately 10% of the world’s population. Because ADs are frequently systemic disorders,
cardiac involvement is common. In this review we focus on typical arrhythmias and their pathogenesis, arrhythmia-associated
mortality, and possible treatment options among selected ADs (sarcoidosis, systemic lupus erythematosus, scleroderma, type 1
diabetes, Graves’ disease, rheumatoid arthritis, ankylosing spondylitis [AS], psoriasis, celiac disease [CD], and inflammatory bowel
disease [IBD]). Rhythm disorders have different underlying pathophysiologies; myocardial inflammation and fibrosis seem to be the
most important factors. Inflammatory processes and oxidative stress lead to cardiomyocyte necrosis, with subsequent electrical and
structural remodeling. Furthermore, chronic inflammation is the pathophysiological basis linking AD to autonomic dysfunction, including
sympathetic overactivation and a decline in parasympathetic function. Autoantibody-mediated inhibitory effects of cellular events
(i.e., potassium or L-type calcium currents, M2 muscarinic cholinergic or β1-adrenergic receptor signaling) can also lead to cardiac
arrhythmia. Drug-induced arrhythmias, caused, for example, by corticosteroids, methotrexate, chloroquine, are also observed among
AD patients. The most common arrhythmia in most AD presentations is atrial arrhythmia (primarily atrial fibrillation), expect for
sarcoidosis and scleroderma, which are characterized by a higher burden of ventricular arrhythmia. Arrhythmia-associated mortality
is highest among patients with sarcoidosis and lowest among those with AS; there are scant data related to mortality in patients with
psoriasis, CD, and IBD.

Key Words: Atrial fibrillation; Autoimmune disease; Immunosuppression; Inflammation; Remodeling

T
he prevalence of autoimmune disease (AD) has
increased significantly over the past 30 years due to
improved detection and surveillance, and currently
affects approximately 7.6–9.4% of the world’s population.1
Because ADs are frequently systemic disorders affecting
different structures and organs, cardiac involvement is
common among AD patients. The structural changes to
heart tissue caused by AD-mediated processes can result in
different manifestations (i.e., ischemia-related symptoms,
heart failure, frequently arrhythmias, and even sudden
cardiac death).
There are different pathophysiological mechanisms
underlying the rhythm disorders. However, myocardial
inflammation and fibrosis seem to be the most important.
Inflammatory processes and oxidative stress lead to cardio-
myocyte necrosis, with subsequent electrical and structural
remodeling. Furthermore, chronic inflammation is the
pathophysiological link between AD and autonomic
dysfunction, including sympathetic overactivation and a
decline in parasympathetic function. Autoantibody-medi-
ated and drug-induced arrhythmias are also frequently
observed among AD patients.2
Currently, there are 80–100 described diseases that occur
as a result of autoimmune responses. In this review we
focus on typical arrhythmias, their prevalence, and their
pathogenesis (Table 1), arrhythmia-associated mortality
(Table 2), and proposed possible treatment options among
selected ADs, namely sarcoidosis, systemic lupus erythe-
matosus (SLE), scleroderma, type 1 diabetes (T1D), Graves’
disease (GD), rheumatoid arthritis (RA), ankylosing
spondylitis (AS), psoriasis, celiac disease (CD), and inflam-
matory bowel disease (IBD).
Sarcoidosis
Sarcoidosis is a multisystem inflammatory disease of
unknown etiology that manifests as a triad of erythema
nodosum, bilateral hilar lymphadenopathy on chest radio-
graph, and joint pain. The prevalence of sarcoidosis ranges
from 2.2 to 160 cases per 100,000 people.3
Ventricular tachycardia (VT) is the most common rhythm
disorder in sarcoidosis, encountered up to 23% of patients.4,5
Atrial arrhythmias are less common, occurring in 15–17%
of patients,2 although small studies have reported a 32%
risk of supraventricular arrhythmia.2 The most common
observed supraventricular arrhythmia is atrial fibrillation

Received December 3, 2019; revised manuscript received January 9, 2020; accepted January 23, 2020; J-STAGE Advance Publication
released online February 26, 2020
1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw (M. Gawałko, P.B., P.L., M. Grabowski, B.K.,
G.O., J.K.), Poland; Department of Electrophysiology, Helios Klinikum Koethen, Koethen (J.K.), Germany
Mailing address:  Jędrzej Kosiuk, MD, PhD, Department of Electrophysiology, Helios Klinkum Koethen, Hallesche Strasse 29, 06366
Koethen, Germany.   E-mail: jedrzejkosiuk@hotmail.com
ISSN-1346-9843   All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.84, May 2020

686 GAWAŁKO M et al.

Table 1.  Summary of Prevalence, Typical Arrhythmias and Their Pathogenesis in Individual Autoimmune Diseases
Prevalence Typical arrhythmias
Autoimmune disease Main pathogenesis
(per 100,000 population) (frequency)
Sarcoidosis 2.2–1603 VT (0.9–28%) Myocardial inflammation, granulomas
Systemic lupus 0.3–24118 Sinus tachycardia (15–50%), Myocardial inflammation, autoantibodies
erythematosus PAC (63.4%)
Scleroderma 3.1–65.934 PVC (20–67%) Myocardial inflammation,
microvascular abnormalities
Type 1 diabetes 6.7–427.550 AF (2–14.9%) Myocardial inflammation, oxidative stress
Graves’ disease 200–50073 AF (2.5–72%) Autonomic dysfunction, autoantibodies
Rheumatoid arthritis 180–1,07090 AF (0.8–18.3%) Myocardial/vascular inflammation,
autonomic activity
Ankylosing spondylitis 102–319104 PAC (2.2–94%), Myocardial inflammation,
PVC (28.6–55%) autonomic activity
Psoriasis 100–200111 AF (2.5–7.1%) Myocardial inflammation
Celiac disease 860126 AF (2.1–3.3%) Myocardial inflammation
Inflammatory bowel disease 0.6–505131 AF (2.8–11.3%) Myocardial inflammation
AF, atrial fibrillation; PAC, premature atrial contractions; PVC, premature ventricular contractions; VT, ventricular tachycardia.

Table 2.  Summary of Arrhythmia-Associated Mortality in Individual Autoimmune Diseases

Arrhythmia-associated mortality
Autoimmune disease References
(% total deaths)
Sarcoidosis 24–65* 142
Systemic lupus erythematosus 7.3*–21 143, 144
Scleroderma 6.0–15 145, 146
Type 1 diabetes 8.0–15 147–149
Graves’ disease 8.0 150
Rheumatoid arthritis 0.8 151
Ankylosing spondylitis 0.5 151
Psoriasis ND
Celiac disease ND
Inflammatory bowel disease ND
*Arrhythmias or conduction disorders. ND, no data.

(AF; 18%), followed by atrial tachycardias (7%), atrial
flutter (5%), and atrioventricular nodal re-entry tachycardia
(2%).6
Postulated proarrhythmic mechanisms include active
inflammation and enhanced automaticity. The re-entrant
pathway can result from active granulomatous inflamma-
tion, but can also be found in association with the healing
of cardiac granulomas in the inactive phase of the disease.7,8
Atrial dilatation or pulmonary involvement are other
factors that contribute to the development of atrial arrhyth-
mias.8 The role of corticosteroids remains inconsistent
because they can improve cardiac function and reduce a
patient’s arrhythmic burden,9 but they also promote fibrosis
of active granulomas and subsequent re-entrant pathways,
leading to recurrent VT.10 In addition, corticosteroids have
been associated with the formation of ventricular aneu-
rysm,2 leading to a vicious circle of ventricular arrhythmias.
Therefore, immunosuppressive therapies are recommended
in cases of resistant arrhythmias or as a steroid-sparing
strategy.10
Amiodarone and sotalol are widely used to treat VT in
patients with sarcoidosis, although adverse reactions
(pulmonary complications and heart block) in patients
with sarcoidosis may limit their applicability.11 Class I
antiarrhythmic agents are not recommended due to frequent
myocardial scarring.12 Pharmacotherapy is also complicated
by the presence of certain acidic acute phase reactants that
bind to drugs with a high acid-base dissociation constant,
thus interfering with serum concentrations.8
Some studies recommend implantable cardioverter-
defibrillator (ICD) placement in patients with sarcoidosis
and non-sustained VT given the high rate of recurrent VT
despite antiarrhythmic and corticosteroid treatment.13
One systemic review that included 91 patients from 6
papers reported beneficial data on catheter ablation of VT
in sarcoidosis and an arrhythmia-free survival rate ranging
from 25% to 57% during a 6- to 33-month follow-up.14 A
more extensive arrhythmogenic substrate with more
advanced cardiac disease at the time of VT ablation may
be the reason for this discrepancy. In that review, the
reported rate of procedural complications did not exceed
4.7–6.4%. The most frequent location of the re-entry circuit
is the paratricuspid area. In patients with predominant
right ventricle (RV) involvement, critical sites in the RV
apex have also been described.14 In patients with epicardial
scarring, an epicardial approach may be necessary to
eliminate VT.15 Therefore, planning the ablation procedure
based on the predominant location of scarring as detected
by late gadolinium-enhanced cardiovascular magnetic
resonance is helpful in eliminating VT in these patients.

Circulation Journal  Vol.84, May 2020

Cardiac Arrhythmias in Autoimmune Diseases
Although there is a high VT relapse rate, catheter ablation
decreases the overall ventricular arrhythmia burden in
88.4% of sarcoidosis patients.16 Willner et al described the
role of catheter ablation for atrial arrhythmia in 9 patients
with cardiac sarcoidosis.17 Of these 9 patients, 7 remained
free from recurrence at 1.8±1.9 years of follow-up and 2
had recurrent atrial arrhythmia. Of the 2 with recurrent
atrial arrhythmia, 1 underwent successful repeat ablation
of atypical atrial flutter and remained free from recurrence
at 2 years, and the second was started on dofetilide and
continued on immunosuppressive therapy and was free of
recurrence at 10 months.17
Nevertheless, resistant VT and severe intractable heart
failure, especially in younger patients, are indications for
cardiac transplantation in patients with sarcoidosis.8
Systemic Lupus Erythematosus
SLE is a chronic inflammatory disease with a prevalence
ranging from 0.3 to 241 per 100,000 population.18 SLE is
described as a triad of fever, joint pain, and butterfly rash.
The causes of premature death associated with SLE are
primarily organ failure or cardiovascular disease secondary
to accelerated atherosclerosis. More than 80% of SLE
patients survive for more than 10 years with proper diag-
nosis and treatment.18
Sinus tachycardia (15–50%), AF, and atrial ectopic beats
are the most frequent cardiac rhythm disorders among
SLE patients.2,19 In the study of Teixeira et al, which
included 317 patients with SLE, frequent Holter-monitoring
abnormalities were observed in approximately 85% of SLE
patients, including supraventricular ectopy (63.4%),
ventricular ectopy (45.8%), bradycardia (31.7%), atrial
tachycardia (15.5%), and AF (2.8%).19 Although, ventricular
arrhythmias are infrequent among SLE patients, the
Systemic Lupus International Collaborating Clinics
Registry revealed a high prevalence of QT prolongation
(15.3%) and increased QT dispersion (38.1%), both of which
are recognized as independent risk factors for the develop-
ment of complex ventricular arrhythmias.20
The pathophysiology of arrhythmias in SLE includes
initial inflammatory cell infiltration and, as the disease
advances, myocardial necrosis and fibrotic replacement.
Consequently, multiple small areas of fibrosis can affect
atrial and ventricular repolarization and conduction, leading
to cardiac rhythm disorders.21 Interestingly, a possible role
of autoantibodies, namely anti-Sjögren’s-syndrome-related
antigen A (Ro/SSA) autoantibodies, in cardiac rhythm
disorders has also been suggested.22 These antibodies can
bind calcium channels and downregulate channel density
and protein expression, which results in deregulation of
intracellular calcium homeostasis and finally apoptosis of
cardiomyocytes.23 Moreover, previous studies reported
an interaction between anti-Ro/SSA antibodies and M3
muscarinic receptors leading to a decrease in parasympa-
thetic activity.19 Increased titers of anti-SS-A/Ro antibodies
described in SLE seem to also be associated with prolonga-
tion of the QTc interval.24 Lazzerini et al reported that in
addition to a high prevalence of QTc interval prolongation,
anti-Ro/SSA-positive patients also have reduced heart rate
variability (HRV) and a high incidence of late ventricular
potentials.22 Case reports have also showed a correlation
between new onset AF and methylprednisolone therapy,25
possibly caused by potassium efflux and the development
of late potentials. Finally, sympathetic hyperactivity indi-
Circulation Journal  Vol.84, May 2020
687
cated by elevated norepinephrine levels could play an
etiologic role in a wide range of diseases, including SLE.26
In general, standard medications for SLE (i.e., gluco-
corticosteroids27 and anti-malarial drugs28) often caused
tachyarrhythmias and QRS prolongation. However, treat-
ment with chloroquine seems to have a protective effect29
because it reduces the velocity of the action potential of the
cells in the conduction system, prolonging the action
potential duration and increasing the refractory period of
Purkinje fibers.30 Furthermore, chloroquine can bind to
and block the Kir2.1 potassium channel, resulting in an
antifibrillatory effect. Conversely, a cumulative chloroquine
dose above median of 1,207 g can lead to cardiac toxicity
and associated electrocardiogram abnormalities.31
Methotrexate and cyclophosphamide may rarely induce
ventricular arrhythmias. Mycophenolate mofetil, tacrolimus,
and rituximab can cause tachycardia (and AF in the case
of rituximab). In contrast, azathioprine and belimumab
are assumed to be safe in terms of arrhythmia induction.32
In this context, adjusting SLE drug therapy may be a valu-
able therapeutic option to reduce the burden of clinically
relevant arrhythmias.
Catheter ablation seems to be safe in drug-resistant AF.2
However, dal Piaz et al reported frequent recurrences of
AF that could be explained by the presence of thickening
of the left atrial (LA) wall associated with extensive atrial
fibrosis.33 Furthermore, electroanatomic mapping fre-
quently reveals large areas of low bipolar voltage in the
anterior wall, septum, posterior wall, and roof (∼52% of
the LA surface).
Scleroderma
Scleroderma may be systemic (SSc), characterized by
abnormal hardening and thickness of the skin and organs,
or localized (LSc), affecting only the skin. The prevalence
of scleroderma varies from 3.1 to 65.9 per 100,000 popu-
lation.34
Patients with scleroderma have been found to have a
higher mean heart rate (81±11 beats/min),35 whereas more
cases of sinus tachycardia are reported in LSc than SSc.36
The most widespread arrhythmias are premature ventricular
contractions (PVC; 20–67%) and VT (7–28%). Supraven-
tricular arrhythmias are also frequent and may be present
in 32–66% of scleroderma patients.2,37 However, the distri-
bution of arrhythmias in pediatric patients is reversed.38
Cardiac involvement is most frequent in SSc.39 Of note, a
wider spatial QRS–T angle >19.3° and ventricular late
potentials have been suggested as independent predictors
of ventricular arrhythmias.40
Myocardial fibrosis, which disrupts the normal electrical
connectivity of cardiac tissue, is the most common patho-
genesis of cardiac rhythm disorders.2,41 Ventricular
arrhythmias are 6-fold more frequent in patients with
severe myocardial scleroderma than in those with mild or
no scleroderma.41 Arrhythmogenesis could result from the
production of anti-β-adrenergic receptor antibodies, which
have been found with idiopathic arrhythmias42 and auto-
nomic dysfunction, often preceding the development of
fibrosis.43 Arrhythmias may also be a consequence of LA
and RV dilation secondary to a higher prevalence of
pulmonary hypertension, more severe mitral and tricuspid
regurgitation, and terminal renal failure.44 Moreover, tran-
sient coronary vasoconstriction, with reversible myocardial
ischemia and dysfunction, has been demonstrated in
688
response to peripheral cold exposure in scleroderma
patients.45
Vasodilator therapy with dihydropyridine-type calcium
channel blockers (CCBs) may improve cardiac perfusion
and ventricular function,39 potentially reducing the burden
of arrhythmias. However, it is worth noting that these
agents may have a negative inotropic effect and cause reflex
tachycardia, and so their use must be closely monitored.
The benefits of ICD implantation in 10 scleroderma
patients with evidence of ventricular arrhythmias were
recently reported: over a 3-year-follow up, 30% of patients
were appropriately reverted by shock delivery.46 In another
study, patients with more than 1,190 PVC per 24 h were
identified as being at high risk of life-threatening arrhyth-
mias.47
Successful treatment with catheter ablation, even in a
hemodynamically unstable scleroderma patients, have been
reported.48 Patients treated with catheter ablation remained
free of VT recurrence for the following 14–25 months.48 The
origin of the re-entrant VT appears to be the RV, primarily
the outflow tract.48 Integration of magnetic resonance
imaging with 3D mapping systems could also greatly facil-
itate electrophysiology procedures.
Type 1 Diabetes
T1D is a chronic disease caused by insulin deficiency
following the destruction of insulin-producing pancreatic
β-cells. The reported prevalence of T1D across the world
ranges from 6.7 to 427.5 per 100,000 population.50
One of the best described arrhythmias among T1D
patients, especially in young females, is AF.51 The risk of
AF in men and women with T1D is 9–13% and 26–50%
higher, respectively, than that in the general population.51
Furthermore, QT interval prolongation has been reported
in T2D.52
The pathophysiology of arrhythmias in T1D includes
inflammation and oxidative stress. Cytokines (interleukin
[IL]-6, IL-2, tumor necrosis factor [TNF]-α, transforming
growth factor [TGF]-β, connective TGF) promote collagen
deposition, myocyte apoptosis, and fibrosis.53 Increased
levels of systemic oxidative stress coupled with production
of reactive oxygen species via the mitochondrial pathway54
induce the nuclear factor (NK)-κB pathway, leading to
atrial remodeling.55 T1D-related oxidative stress attenuates
potassium, L-type calcium, and sodium-potassium and
sodium-calcium exchanger currents, resulting in a small
depolarization in the resting membrane potential that pro-
longs the action potential duration.56 Moreover, advanced
glycation end-products and their receptors,57 the Rho-
associated protein kinase pathway,58 and decreased expres-
sion of peroxisome proliferator activated receptor γ59 and
the paired-like homeodomain transcription factor 2 (Pitx2)
gene60 can play a role in the development of atrial fibrosis
in diabetic hearts. In addition, left ventricular dysfunction
and hypertrophy, the first proarrhythmic changes in patients
with impaired glucose tolerance, increase LA afterload
pressure, leading to atrial dilation and AF.61 In addition,
in many animal models, increased expression of connexin-43
and cathepsin A (the expression of which is associated with
impaired LA emptying function, increased LA fibrosis,
and regions of slow conduction) has been noted as a poten-
tial proarrhythmic mechanism.62,63 T1D-related enhanced
sympathetic and decreased parasympathetic activity are
also crucial contributors to increased AF in diabetics.64
Circulation Journal  Vol.84, May 2020
GAWAŁKO M et al.
Moreover, sudden sympathetic activation in response to
hypoglycemia also contributes to the occurrence of AF
and ventricular arrhythmias in certain cases.65
It has been suggested that stringent glycemic control
could reduce the incidence of AF in T2D.66 However, the
Action to Control Cardiovascular Risk in Diabetes trial
failed to show a benefit of intensive vs. standard glycemic
control on the occurrence of new-onset AF in T2D.67
Nevertheless, various antidiabetic agents have been shown
to reduce AF risk since metformin,68 rosiglitazone, piogli-
tazone,69 and thiazolidinediones70 were reported to attenuate
oxidative stress, inflammation, fibrosis, and associated atrial
remodeling.
Compared with antiarrhythmic drug therapy, catheter
ablation of AF was associated with improved quality of
life, reduced AF hospitalizations (8.6% vs. 34.3%; P=0.01)
and a decreased likelihood of AF recurrence (20% vs.
57.1%; P=0.001).70 However, in the study of Tang et al,
pulmonary vein isolation was similarly effective in patients
with and without T2D, but T2D patients were more prone
to develop post-procedural complications.71 Of note, in
patients undergoing catheter ablation for AF, maintenance
of sinus rhythm was higher and the need for a second
ablation was lower in the group of patients treated with
pioglitazone.68 Finally, in patients with T1D/T2D (no
information regarding diabetes type in the article), low-
voltage areas were more frequently observed than in the
control group.72
Graves’ Disease
GD is characterized by hyperthyroidism due to circulating
thyrotropin receptor antibodies. The annual prevalence of
GD ranges from 200 to 500 cases per 100,000 population.73
The most common cardiac rhythm disorder among GD
patients is AF.74 Sawin et al reported a 2.8-fold increased
risk of AF in individuals with subclinical hyperthyroid
aged >60 years.75 There is also a single report of ventricular
arrhythmias among GD patients.76
AF in hyperthyroid patients is explained by a decreased
atrial refractory period, increased sympathetic tone with
decreased HRV, and automaticity in the pulmonary vein.77
Watanabe et al found that decreased the atrial refractory
period is caused by thyroid hormone-mediated decreases
in the expression of L-type calcium channel mRNA and
increased expression of the Kv1.5 potassium channel.78 The
presence of autoantibodies to both β1/2-adrenergic and M2
muscarinic cholinergic receptors results in increased
sympathetic function and a decreased atrial refractory
period.79 The correlation between hyperthyroidism and
ventricular arrhythmia is explained by the effects of thyroid
hormone on cardiac myocyte Na+/K+-ATPase, further
increasing intracellular potassium levels, hyperpolarizing
the membrane and prolonging repolarization, which
manifests as a prolonged QTc interval.80
Berker et al reported that improvements in atrial conduc-
tion were associated with euthyroidism regardless of the
chosen therapy.81 Patients with GD and AF who become
hypothyroid are more likely to revert to sinus rhythm than
those who are rendered euthyroid during this period.82
Surgical treatment of GD resulted in rapid clinical
improvement of impaired left ventricular systolic function
as well as the resolution of tachycardia and AF in 68.8%
and 100% of patients, respectively.83 Disopyramide, bepridil,
and prednisone therapy resulted in conversion to sinus
Cardiac Arrhythmias in Autoimmune Diseases
rhythm in 15%, 81.3%, and 86% of patients, respectively.84
In addition, prednisone therapy proved to be beneficial in
reverting AF into sinus rhythm among GD patients, with
a reversion rate of 86% and a mean reversion time of 3.8
months.85
Ma et al studied the efficacy of circumferential pulmonary
vein ablation and found that AF relapsed over a mean
follow-up period of 15.8 months in 44% of 16 patients with
thyrotoxic AF.86 In addition, non-pulmonary vein triggers
are significantly more often observed in patients with
hyperthyroidism and there is a higher risk of occurrence of
AF after a single ablation compared to controls.87 It is
worth noting that elevated thyroxin levels increase the risk
of a thrombotic event by increasing Factor VIII, Factor IX,
fibrinogen, von Willebrand factor, and plasminogen acti-
vator inhibitor-1 levels and by decreasing antithrombin III,88
and anticoagulation treatment may be considered.89
Rheumatoid Arthritis
RA primarily attacks the synovial tissues within the small
joints, leading to limitation of movements. The prevalence
of RA varies between 180 and 1,070 per 100,000 popula-
tion.90
The most frequent arrhythmia among RA patients is
AF, especially in young (<50 years) females91 with sedimen-
tation rates >60 mm/h92 or anti-TNF-α antibodies.93 In a
Danish cohort study of 4,182,335 participants, including
18,247 with RA, the overall incidence of AF was approxi-
mately 40% higher than in the general population. 94
However, in the subsequent meta-analysis of 3 retrospective
cohort studies, the pooled risk ratio of developing AF in
patients with RA vs. controls was only 1.29, because in 2
of those studies no increased risk of incident AF was
observed after adjusting for comorbidity and medication.95
Although described by smaller cohort studies, other fre-
quent arrhythmias among RA patients are PVC and VT.96
The basis for rhythm disorder is diffuse cardiac involve-
ment (rheumatoid nodules or inflammatory lesions), as
well as coronary vasculitis and coronary atherosclerotic
disease, which lead to perfusion defects of the myocardium
with proarrhythmic effects.97 Moreover, antibodies against
the cardiac conduction system,98 found in 35% of patients
with RA, which increase P-wave dispersion (PWD)99 and
LA diameter,100 may play important an role in conduction
abnormalities in RA patients. Increased sympathetic and
decreased parasympathetic activity could play a crucial
role in the development of VT in RA patients.101 Reports
suggest that the anti-inflammatory drug infliximab may be
associated with new-onset ventricular tachyarrhythmias.93
Early therapy with disease-modifying antirheumatic
drugs has been demonstrated to have beneficial effects on
the lipid profile and to reduce atherosclerotic processes and
endothelial dysfunction by decreasing inflammation.102
The success rate of catheter ablation for AF in patients
with RA is comparable to that in patients without RA.
However, RA patients tend to develop early atrial tachyar-
rhythmia recurrence after AF ablation compared with
controls, as shown in a small group of patients (n=15).103
Ankylosing Spondylitis
AS is a chronic inflammatory disorder involving the sacro-
iliac joints and spine that leads to their progressive stiffening.
The prevalence of AS ranges from 102 to 319 per 100,000
Circulation Journal  Vol.84, May 2020
689
population.104
AS patients have a higher probability of developing
atrioventricular re-entry tachycardia than the general
population.105 The frequency of Wolff-Parkinson-White
syndrome in AS patients has been reported to be 6.24 per
1,000 patients. Moreover, patients with paroxysmal supra-
ventricular tachycardia are reported to develop ≥1 other
kind of arrhythmia, including premature atrial contractions
(50%), PVC (28.6%), tachycardia-bradycardia (14.3%), AF
(14.3%), and atrial flutter (7.1%).105 All these AS patients
were diagnosed with higher disease activity than controls.105
In addition, the frequency of both PVC and premature
atrial contractions was reported to be significantly higher
AS patients than in those without AS, which correlates
with QT dispersion.106
The pathogenesis of paroxysmal supraventricular tachy-
cardia usually reflects the presence of re-entry of cardiac
conduction secondary to inflammatory processes, fibro-
muscular proliferation, and fibrotic scarring, as well as
increased automaticity and trigger activity.107 It has been
also recognized that human leukocyte antigen (HLA) B27
is associated with the initiation of arrhythmias by increasing
platelet adhesion to vessel walls, thus leading to perfusion
defects.108
There is only 1 case report describing the successful
termination of a monomorphic VT episode at the antero-
basal site of the left ventricle without recurrence after
1-month.109 This is in line with histopathological studies,
which report that the left ventricle is involved in more than
50% of cases.110
Psoriasis
Psoriasis is a chronic inflammatory condition characterized
by excessive growth of the epidermal layer of the skin and
associated patches of abnormal, thickened skin. The
reported prevalence of psoriasis ranges between 100 and
200 per 100,000 population.111
Patients with psoriasis are more susceptible to AF than
the general population,112,113 with a severity-adjusted risk
of 1.50–2.98 in patients aged <50 years and 1.16–1.29 in
those aged ≥50 years.114 Commonly seen arrhythmias in
patients are also single supraventricular beats115 and
ventricular arrhythmias, including VT related to commonly
observed increased PWD and QT dispersion.116
Chronic inflammation mediated by systemic inflamma-
tory cytokines, such as TNF-α, IL-6, and IL-17, is the most
important contributor linking psoriasis to increased AF
incidence.117 Another structural remodeling factor with
increased bioactivity in psoriasis is platelet-derived growth
factor α (PDGFα), which promotes cell proliferation and
collagen expression in cardiac fibroblasts. Moreover, TNF-α
and PDGFα are responsible for electronic remodeling:
TNF-α interferes with calcium influx into pulmonary vein
cardiomyocytes,118 whereas PDGFα reduces the action
potential duration and calcium transients.119 Sympathetic
nervous system dysregulation,120 inflammation-related
structural mitral valve changes,121 and depression122 may be
other possible reasons for the high incidence of AF among
those with psoriasis.
Methotrexate and TNF inhibitors are associated with a
decreased risk of cardiovascular disease morbidity and
mortality, whereas ustekinumab appears to be neutral.123
Patients using TNF inhibitors have a lower risk of cardio-
vascular events that those undergoing phototherapy. In
690
addition, phototherapy has been reported to have no
major cardiovascular effect and may reduce levels of
proinflammatory cytokines.124 Statins, with anti-inflamma-
tory and antioxidative effects, also reduce the incidence of
both AF and psoriasis.125
Celiac Disease
CD is a life-long gluten-sensitive AD primarily involving
the small intestine, but with potential effects in other organ
systems, genetically affecting susceptible individuals. The
worldwide prevalence of CD is 860 per 100,000 popula-
tion.126
The most common cardiac arrhythmia in CD is AF,
with a reported incidence 30% higher than in the general
population.127 An elevated risk of ventricular arrhythmias
(multiform and repetitive couplets of PVC) has been also
reported.128
This increased risk of AF has been attributed to inflam-
mation and fibrosis, the coexistence of other autoimmune
conditions (T1D, RA, and thyroid disease),127 and hyper-
homocysteinemia, resulting from vitamin B deficiency,
which affects sodium and potassium channels in the atria.129
In the study of Corazza et al, a QTc interval >440 ms,
associated with the development of ventricular arrhythmias,
was found in 32% of 53 untreated coeliac patients but in
only 3% of 30 patients on a gluten-free diet.130 These find-
ings are in line with those of Frustaci et al, who observed
downgrading from Lown Class III–IVa to I in 187 patients
following a gluten-free diet alone.128
Inflammatory Bowel Disease
IBD is a chronic, inflammatory disease of the gastrointes-
tinal tract and includes ulcerative colitis and Crohn’s
disease. The annual prevalence of IBD is 4.9–505 per
100,000 population for ulcerative colitis, and 0.6–322 per
100,000 population for Crohn’s disease.131
AF represents the most common sustained cardiac
arrhythmia among patients with IBD, and its incidence
increases more than 2-fold during active flare-ups of IBD.132
The very powerful inflammatory cytokines implicated
in AF development are C-reactive protein (CRP) and
IL-6.133 Studies suggest that IL-6 is significantly correlated
with increased LA size134 by stimulating matrix metallo-
proteinase-2,135 whereas increased circulating CRP may
localize in atrial tissue, inducing myocarditis136 and electrical
changes in the atrium.137 Furthermore, PWD and electro-
mechanical delay, well-described predictors of AF, were
high in IBD patients.138 These results confirm the signifi-
cant decrease in parasympathetic function in patients with
IBD as an important factor triggering arrhythmia.139
The observed prolongation in QT interval and significant
QT dispersion in IBD patients using cardiotoxic medica-
tions like infliximab or ciprofloxacin140 highlights the need
for the continued surveillance of these patients. There are
some reports in the literature focusing on the effects of
azathioprine on ion channels, which may be the cause of
cardiac rhythm disturbance.141
Conclusions
Arrhythmias are important and frequent manifestations of
cardiac involvement in patients with AD. Early recognition
of life-threatening arrhythmias is crucial to improve the
Circulation Journal  Vol.84, May 2020
GAWAŁKO M et al.
overall prognosis of AD patients. It is of note that most of
cardiac rhythm disorders are transient and can be the first
presentation of autoimmune conditions, resolving when
the underlying disease is controlled. Further prospective
studies and unifying registers encompassing ADs with their
accompanying arrhythmias are warranted in order to
explore the pathogenesis and to improve the early diagnosis
of cardiac rhythm disorders.
Sources of Funding
None.
Conflict of Interest
None declared.
References
  1. Lerner A, Jeremias P, Matthias T. The world incidence and
prevalence of autoimmune diseases is increasing. Int J Celiac
Dis 2015; 3: 151 – 155.
  2. Seferovic PM, Ristic AD, Maksimovic R, Simeunovic DS,
Ristic GG, Radovanovic G, et al. Cardiac arrhythmias and
conduction disturbances in autoimmune rheumatic diseases.
Rheumatology 2006; 45: iv39 – iv42.
   3. Arkema EV, Cozier YC. Epidemiology of sarcoidosis: Current
findings and future directions. Ther Adv Chronic Dis 2018; 9:
227 – 240.
   4. Furushima H, Chinushi M, Sugiura H, Kasai H, Washizuka T,
Aizawa Y. Ventricular tachyarrhythmia associated with cardiac
sarcoidosis: Its mechanisms and outcome. Clin Cardiol 2004; 27:
217 – 222.
   5. Salama A, Abdullah A, Wahab A, Eigbire G, Hoefen R, Alweis
R. Cardiac sarcoidosis and ventricular arrhythmias. A rare
association of a rare disease. A retrospective cohort study
from the National Inpatient Sample and current evidence for
management. Cardiol J, doi:10.5603/CJ.a2018.0104.
  6. Viles-Gonzalez JF, Pastori L, Fischer A, Wisnivesky JP,
Goldman MG, Mehta D. Supraventricular arrhythmias in
patients with cardiac sarcoidosis prevalence, predictors, and
clinical implications. Chest 2013; 143: 1085 – 1090.
   7. Birnie DH, Kandolin R, Nery PB, Kupari M. Cardiac manifes-
tations of sarcoidosis: Diagnosis and management. Eur Heart J
2017; 38: 2663 – 2670.
   8. Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP.
Cardiac sarcoidosis: A comprehensive review. Arch Med Sci
2011; 7: 546 – 554.
  9. Yodogawa K, Seino Y, Ohara T, Takayama H, Katoh T,
Mizuno K. Effect of corticosteroid therapy on ventricular
arrhythmias in patients with cardiac sarcoidosis. Ann Noninvasive
Electrocardiol 2011; 16: 140 – 147.
  10. Winters SL, Cohen M, Greenberg S, Stein B, Curwin J, Pe E, et al.
Sustained ventricular tachycardia associated with sarcoidosis:
Assessment of the underlying cardiac anatomy and the prospective
utility of programmed ventricular stimulation, drug therapy
and an implantable antitachycardia device. J Am Coll Cardiol
1991; 18: 937 – 943.
  11. Kopriva P, Griva M, Tüdös Z. Management of cardiac sarcoid-
osis: A practical guide. Cor et Vasa 2018; 60: e155 – e164.
  12. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D,
Barker AH, et al. Mortality and morbidity in patients receiving
encainide, flecainide, or placebo: The Cardiac Arrhythmia
Suppression Trial. N Engl J Med 1991; 324: 781 – 788.
  13. Doughan AR, Williams BR. Cardiac sarcoidosis. Heart 2006;
92: 282 – 288.
 14. Papageorgiou N, Providência R, Bronis K, Dechering DG,
Srinivasan N, Eckardt L, et al. Catheter ablation for ventricular
tachycardia in patients with cardiac sarcoidosis: A systematic
review. Europace 2018; 20: 682 – 691.
 15. Muser D, Liang JJ, Pathak RK, Magnani S, Castro SA,
Hayashi T, et al. Long-term outcomes of catheter ablation of
ventricular tachycardia in patients with cardiac sarcoidosis.
Circ Arrhythm Electrophysiol 2016; 9: pii: e004333.
 16. Bogun FM, Desjardins B, Good E, Gupta S, Crawford T,
Oral H, et al. Delayed-enhanced magnetic resonance imaging
in nonischemic cardiomyopathy: Utility for identifying the
ventricular arrhythmia substrate. J Am Coll Cardiol 2009; 53:
Cardiac Arrhythmias in Autoimmune Diseases
1138 – 1145.
  17. Willner JM, Viles-Gonzalez JF, Coffey JO, Morgenthau AS,
Mehta D. Catheter ablation of atrial arrhythmias in cardiac  
sarcoidosis. J Cardiovasc Electrophysiol 2014; 25: 958 – 963.
  18. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The
worldwide incidence and prevalence of systemic lupus erythe-
matosus: A systematic review of epidemiological studies.  
Rheumatology (Oxford) 2017; 56: 1945 – 1961.
 19. Teixeira RA, Borba EF, Bonfá E, Martinelli Filho M.
Arrhythmias in systemic lupus erythematosus. Rev Bras Reumatol
2010; 50: 81 – 89.
  20. Bourré-Tessier J, Clarke AE, Huynh T, Bernatsky S, Joseph L,  
Belisle P, et al. Prolonged corrected QT interval in anti-Ro/
SSA-positive adults with systemic lupus erythematosus. Arthritis
Care Res (Hoboken) 2011; 63: 1031 – 1037.
  21. Ashrafi R, Garg P, McKay E, Gosney J, Chuah S, Davis G.
Aggressive cardiac involvement in systemic lupus erythematosus:  
A case report and a comprehensive literature review. Cardiol
Res Pract 2011; 2011: 578390.
  22. Lazzerini PE, Acampa M, Guideri F, Capecchi PL, Campanella  
V, Morozzi G, et al. Prolongation of the corrected QT interval
in adult patients with anti-Ro/SSA-positive connective tissue
diseases. Arthritis Rheum 2004; 50: 1248 – 1252.
 23. Santos-Pardo I, Villuendas R, Salvador-Corres I, Martínez-  
Morillo M, Olivé A, Bayes-Genis A. Anti-Ro/SSA antibodies and
cardiac rhythm disturbances: Present and future perspectives.
Int J Cardiol 2015; 184: 244 – 250.
  24. Didier K, Bolko L, Giusti D, Toquet S, Robbins A, Antonicelli  
F, et al. Autoantibodies associated with connective tissue
diseases: What meaning for clinicians? Front Immunol 2018; 9:
541.
  25. Romano C, Sirotti V, Farinaro V, Luiso V, Solaro E, De Sio C,  
et al. Atrial fibrillation following therapy with high-dose i.v.
methylprednisolone: A brief case-based review. Eur J Rheumatol
2017; 4: 231 – 233.  
 26. Barnado A, Carroll RJ, Casey C, Wheless L, Denny JC,
Crofford LJ. Phenome-wide association studies uncover a novel
association of increased atrial fibrillation in male patients with
systemic lupus erythematosus. Arthritis Care Res (Hoboken)  
2018; 70: 1630 – 1636.
  27. Salem JE, Alexandre J, Bachelot A, Funck-Brentano C. Influence
of steroid hormones on ventricular repolariza-tion. Pharmacol
Ther 2016; 167: 38 – 47.  
  28. Morgan ND, Patel SV, Dvorkina O. Suspected hydroxychloro-
quine-associated QT-interval prolongation in a patient with
systemic lupus erythematosus. J Clin Rheumatol 2013; 19: 286 –  Korean Med Sci 2012; 27: 215 – 217.
288.  
  29. Wozniacka A, Cygankiewicz I, Chudzik M, Sysa-Jedrzejowska
A, Wranicz JK. The cardiac safety of chloroquine phosphate
treatment in patients with systemic lupus erythematosus: The
influence on arrhythmia, heart rate variability and repolarization  
parameters. Lupus 2006; 15: 521 – 525.
  30. McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma
Z. Electrocardiogram abnormalities related to anti-malarials in
systemic lupus erythematosus. Clin Exp Rheumatol 2018; 36:
545 – 551.  
  31. Noujaim SF, Stuckey JA, Ponce-Balbuena D, Ferrer-Villada T,
López-Izquierdo A, Pandit SV, et al. Structural bases for the
different anti-fibrillatory effects of chloroquine and quinidine.
Cardiovasc Res 2011; 89: 862 – 869.
 32. US Food and Drug Administration (FDA). https://www.  
accessdata.fda.gov/scripts/cder/daf/index.cfm (accessed November
1, 2019).
  33. dal Piaz EC, Casagranda G, Ravanelli D, Marini M, Valentini A,
Del Greco M. Extensive atrial fibrosis in a patient with systemic  
lupus erythematosus and atrial fibrillation. HeartRhythm Case
Rep 2015; 1: 206 – 208.
 34. Barnes J, Mayes MD. Epidemiology of systemic sclerosis:
Incidence, prevalence, survival, risk factors, malignancy, and  
environmental triggers. Curr Opin Rheumatol 2012; 24: 165 – 170.
 35. Wranicz JK, Strzondała M, Zielińska M, Cygankiewicz I,
Ruta J, Dziankowska-Bartkowiak B, et al. Evaluation of early  
cardiovascular involvement in patients with systemic sclerosis.
Przegl Lek 2000; 57: 389 – 392 (in Polish).
  36. Borowiec A, Dabrowski R, Wozniak J, Jasek S, Chwyczko T,
Kowalik I, et al. Cardiovascular assessment of asymptomatic
patients with juvenile-onset localized and systemic scleroderma:  
10 years prospective observation. Scand J Rheumatol 2012; 41:
33 – 38.
  37. Kostis JB, Seibold JR, Turkevich D, Masi AT, Grau RG, Medsger  
Circulation Journal  Vol.84, May 2020
691
TA Jr, et al. Prognostic importance of cardiac arrhythmias in
systemic sclerosis. Am J Med 1988; 84: 1007 – 1015.
38. Wozniak J, Dabrowski R, Luczak D, Kwiatkowska M, Musiej-
Nowakowska E, Kowalik I, et al. Evaluation of heart rhythm
variability and arrhythmia in children with systemic and localized
scleroderma. J Rheumatol 2009; 36: 191 – 196.
39. Allanore Y, Meune C, Vonk MC, Airo P, Hachulla E,
Caramaschi P, et al. Prevalence and factors associated with left
ventricular dysfunction in the EULAR scleroderma trial and
research group (EUSTAR) database of patients with systemic
sclerosis. Ann Rheum Dis 2010; 69: 218 – 221.
40. Gialafos E, Konstantopoulou P, Voulgari C, Giavri I,
Panopoulos S, Vaiopoulos G, et al. Abnormal spatial QRS-T
angle, a marker of ventricular repolarisation, predicts serious
ventricular arrhythmia in systemic sclerosis. Clin Exp Rheumatol
2012; 30: 327 – 331.
41. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial
lesions of progressive systemic sclerosis: A cause of cardiac
dysfunction. Circulation 1976; 53: 483 – 490.
42. Brisinda D, Sorbo AR, Venuti A, Ruggieri MP, Manna R,
Fenici P, et al. Anti-β-adrenoceptors autoimmunity causing
‘idiopathic’ arrhythmias and cardiomyopathy. Circ J 2012; 76:
1345 – 1353.
43. Cozzolino D, Naclerio C, Iengo R, D’Angelo S, Cuomo G,
Valentini G. Cardiac autonomic dysfunction precedes the
development of fibrosis in patients with systemic sclerosis.
Rheumatology (Oxford) 2002; 41: 586 – 588.
44. Muresan L, Petcu A, Pamfil C, Muresan C, Rinzis M, Mada
RO, et al. Cardiovascular profiles of scleroderma patients with
arrhythmias and conduction disorders. Acta Reumatol Port
2016; 41: 26 – 39.
45. Follansbee WP, Zerbe TR, Medsger TA Jr. Cardiac and skeletal
muscle disease in systemic sclerosis (scleroderma): A high risk
association. Am Heart J 1993; 125: 194 – 203.
46. Bernardo P, Conforti ML, Bellando-Randone S, Pieragnoli P,
Blagojevic J, Kaloudi O, et al. Implantable cardioverter defibril-
lator prevents sudden cardiac death in systemic sclerosis. J
Rheumatol 2011; 38: 1617 – 1621.
47. De Luca G, Bosello S, Leone AM, Gabrielli F, Pelargonio G,
Inzani F, et al. Life-threatening arrhythmias in a scleroderma
patient: The role of myocardial inflammation in arrhythmic
outburst. Scand J Rheumatol 2017; 46: 78 – 80.
48. Chung HH, Kim JB, Hong SH, Lee HJ, Joung B, Lee MH.
Radiofrequency catheter ablation of hemodynamically unstable
ventricular tachycardia associated with systemic sclerosis. J
49. Chatzidou S, Repasos V, Palios J, Plastiras S. Usefulness of
cardiovascular magnetic resonance imaging in supraventricular
tachycardia ablation in a scleroderma patient. Hellenic J Cardiol
2017; 58: 159 – 160.
50. Frese T, Sandholzer H. The epidemiology of type 1 diabetes
mellitus. In: Escher A, Li A, editors. Type 1 diabetes. IntechOpen.
2013. https://www.intechopen.com/books/type-1-diabetes/
the-epidemiology-of-type-1-diabetes-mellitus (accessed November
1, 2019).
51. Dahlqvist S, Rosengren A, Gudbjörnsdottir S, Pivodic A,
Wedel H, Kosiborod M, et al. Risk of atrial fibrillation in
people with type 1 diabetes compared with matched controls
from the general population: A prospective case-control study.
Lancet Diabetes Endocrinol 2017; 5: 799 – 807.
52. Cardoso CR, Salles GF, Deccache W. Prognostic value of QT
interval parameters in type 2 diabetes mellitus: Results of a
long-term follow-up prospective study. J Diabetes Complications
2003; 17: 169 – 178.
53. Şerban RC, Scridon A. Data linking diabetes mellitus and atrial
fibrillation: How strong is the evidence? From epidemiology
and pathophysiology to therapeutic implications. Can J Cardiol
2018; 34: 1492 – 1502.
54. Zhang Q, Liu T, Ng CY, Li G. Diabetes mellitus and atrial
remodeling: Mechanisms and potential upstream therapies.
Cardiovasc Ther 2014; 32: 233 – 241.
55. Fu H, Li G, Liu C, Li J, Cheng L, Yang W, et al. Probucol
prevents atrial remodeling by inhibiting oxidative stress and
TNF-α/NF-κB/TGF-β signal transduction pathway in alloxan-
induced diabetic rabbits. J Cardiovasc Electrophysiol 2015; 26:
211 – 222.
56. Yaras N, Turan B. Interpretation of relevance of sodium-calcium
exchange in action potential of diabetic rat heart by mathematical
model. Mol Cell Biochem 2005; 269: 121 – 129.
57. Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K,
692
Takamura M, et al. AGEs-RAGE system mediates atrial struc-
tural remodeling in the diabetic rat. J Cardiovasc Electrophysiol
2008; 19: 415 – 420.
  58. Chen J, Li Q, Dong R, Gao H, Peng H, Wu Y. The effect of the
Ras homolog gene family (Rho), member A/Rho associated
coiled-coil forming protein kinase pathway in atrial fibrosis of
type 2 diabetes in rats. Exp Ther Med 2014; 8: 836 – 840.
  59. Chen X, Bing Z, He J, Jiang L, Luo X, Su Y, et al. Downregula-
tion of peroxisome proliferator-activated receptor-gamma
expression in hypertensive atrial fibrillation. Clin Cardiol 2009;
32: 337 – 345.
  60. Scridon A, Fouilloux-Meugnier E, Loizon E, Rome S, Julien C,
Barrès C, et al. Long-standing arterial hypertension is associated
with Pitx2 down-regulation in a rat model of spontaneous atrial
tachyarrhythmias. Europace 2015; 17: 160 – 165.
  61. Shimabukuro M, Higa N, Asahi T, Yamakawa K, Oshiro Y,
Higa M, et al. Impaired glucose tolerance, but not impaired
fasting glucose, underlies left ventricular diastolic dysfunction.
Diabetes Care 2011; 34: 686 – 690.
 62. Mitasíková M, Lin H, Soukup T, Imanaga I, Tribulová N.
Diabetes and thyroid hormones affect connexin-43 and PKC-ε
expression in rat heart atria. Physiol Res 2009; 58: 211 – 217.
  63. Linz D, Hohl M, Dhein S, Ruf S, Reil JC, Kabiri M, et al.
Cathepsin A mediates susceptibility to atrial tachyarrhythmia
and impairment of atrial emptying function in Zucker diabetic
fatty rats. Cardiovasc Res 2016; 110: 371 – 380.
 64. Otake H, Suzuki H, Honda T, Maruyama Y. Influences of
autonomic nervous system on atrial arrhythmogenic substrates
and the incidence of atrial fibrillation in diabetic heart. Int
Heart J 2009; 50: 627 – 641.
  65. Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E,
Hanefeld M. Risk of and risk factors for hypoglycemia and
associated arrhythmias in patients with type 2 diabetes and
cardiovascular disease: A cohort study under real-world condi-
tions. Acta Diabetol 2015; 52: 889 – 895.
  66. Fatemi O, Yuriditsky E, Tsioufis C, Tsachris D, Morgan T,
Basile J, et al. Impact of intensive glycemic control on the
incidence of atrial fibrillation and associated cardiovascular
outcomes in patients with type 2 diabetes mellitus (from the
Action to Control Cardiovascular Risk in Diabetes Study). Am
J Cardiol 2014; 114: 1217 – 1222.
  67. Chang SH, Wu LS, Chiou MJ, Liu JR, Yu KH, Kuo CF, et al.
Association of metformin with lower atrial fibrillation risk
among patients with type 2 diabetes mellitus: A population-based
dynamic cohort and in vitro studies. Cardiovasc Diabetol 2014;
13: 123.
  68. Gu J, Liu X, Wang X, Shi H, Tan H, Zhou L, et al. Beneficial
effect of pioglitazone on the outcome of catheter ablation in
patients with paroxysmal atrial fibrillation and type 2. Europace
2011; 13: 1256 – 1261.
  69. Chao TF, Leu HB, Huang CC, Chen JW, Chan WL, Lin SJ, et
al. Thiazolidinediones can prevent new onset atrial fibrillation
in patients with non-insulin dependent diabetes. Int J Cardiol
2012; 156: 199 – 202.
  70. Forleo GB, Mantica M, De Luca L, Leo R, Santini L, Panigada
S, et al. Catheter ablation of atrial fibrillation in patients with
diabetes mellitus type 2: Results from a randomized study
comparing pulmonary vein isolation versus antiarrhythmic drug
therapy. J Cardiovasc Electrophysiol 2009; 20: 22 – 28.
  71. Tang RB, Dong JZ, Liu XP, Fang DP, Long DY, Liu XH, et
al. Safety and efficacy of catheter ablation of atrial fibrillation
in patients with diabetes mellitus: Single center experience. J
Interv Card Electrophysiol 2006; 17: 41 – 46.
  72. Kosiuk J, Dinov B, Kornej J, Acou WJ, Schönbauer R, Fiedler
L, et al. Prospective, multicenter validation of a clinical risk
score for left atrial arrhythmogenic substrate based on voltage
analysis: DR-FLASH score. Heart Rhythm 2015; 12: 2207 – 2212.
 73. Cooper GS, Stroehla BC. The epidemiology of autoimmune
diseases. Autoimmun Rev 2003; 2: 119 – 125.
  74. Shimizu T, Koide S, Noh JY, Sugino K, Ito K, Nakazawa H.
Hyperthyroidism and the management of atrial fibrillation.
Thyroid 2002; 12: 489 – 493.
  75. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach
P, et al. Low serum thyrotropin concentrations as a risk factor
for atrial fibrillation in older persons. N Engl J Med 1994; 331:
1249 – 1252.
 76. Kobayashi H, Haketa A, Abe M, Tahira K, Hatanaka Y,
Tanaka S, et al. Unusual manifestation of Graves’ disease:
Ventricular fibrillation. Eur Thyroid J 2015; 4: 207 – 212.
  77. Chen YC, Chen SA, Chen YJ, Chang MS, Chan P, Lin CI.
Circulation Journal  Vol.84, May 2020
GAWAŁKO M et al.
Effects of thyroid hormone on the arrhythmogenic activity of
pulmonary vein cardiomyocytes. J Am Coll Cardiol 2002; 39:
366 – 372.
 78. Watanabe H, Ma M, Washizuka T, Komura S, Yoshida T,
Hosaka Y, et al. Thyroid hormone regulates mRNA expression
and currents of ion channels in rat atrium. Biochem Biophys Res
Commun 2003; 308: 439 – 444.
 79. Jia G, Sowers JR. Autoantibodies of β-adrenergic and M2
cholinergic receptors: Atrial fibrillation in hyperthyroidism.
Endocrine 2015; 49: 301 – 303.
  80. Reddy V, Taha W, Kundumadam S, Khan M. Atrial fibrillation
and hyperthyroidism: A literature review. Indian Heart J 2017;
69: 545 – 550.
  81. Berker D, Işik S, Canbay A, Aydin Y, Tütüncü Y, Delibaşi T,
et al. Comparison of antithyroid drugs efficacy on P wave
changes in patients with Graves’ disease. Anadolu Kardiyol Derg
2009; 9: 298 – 303.
 82. Scott GR, Forfar JC, Toft AD. Graves’ disease and atrial
fibrillation: The case for even higher doses of therapeutic
iodine-131. Br Med J (Clin Res Ed) 1984; 289: 399 – 400.
  83. Gauthier JM, Mohamed HE, Noureldine SI, Nazari-Shafti TZ,
Thethi TK, Kandil E. Impact of thyroidectomy on cardiac
manifestations of Graves’ disease. Laryngoscope 2016; 126:
1256 – 1259.
  84. Kunii Y, Uruno T, Matsumoto M, Mukasa K, Noh J, Ito K, et al.
Pharmacological conversion of atrial fibrillation in the patients
of Graves’ disease. Tokai J Exp Clin Med 2012; 37: 107 – 112.
  85. Wei H, Li M, Qiu M. Treatment of hyperthyroid atrial fibrillation
associated with Graves disease by prednisone. Zhonghua Yi Xue
Za Zhi 2002; 82: 810 – 812 (in Chinese).
  86. Ma CS, Liu X, Hu FL, Dong JZ, Liu XP, Wang XH, et al.
Catheter ablation of atrial fibrillation in patients with hyperthy-
roidism. J Interv Card Electrophysiol 2007; 18: 137 – 142.
  87. Wongcharoen W, Lin YJ, Chang SL, Lo LW, Hu YF, Chung
FP, et al. History of hyperthyroidism and long-term outcome
of catheter ablation of drug-refractory atrial fibrillation. Heart
Rhythm 2015; 12: 1956 – 1962.
  88. Horacek J, Maly J, Svilias I, Smolej L, Cepkova J, Vizda J, et al.
Prothrombotic changes due to an increase in thyroid hormone
levels. Eur J Endocrinol 2015; 172: 537 – 542.
  89. Hansten PD. Oral anticoagulants and drugs which alter thyroid
function. Drug Intelligence Clin Pharm 1980; 14: 331 – 334.
  90. Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence
of rheumatoid arthritis, based on the 1987 American College of
Rheumatology criteria: A systematic review. Semin Arthritis
Rheum 2006; 36: 182 – 188.
  91. Bacani AK, Crowson CS, Roger VL, Gabriel SE, Matteson EL.
Increased incidence of atrial fibrillation in patients with
rheumatoid arthritis. Biomed Res Int 2015; 2015: 809514.
  92. Pizzuto K, Averns HL, Baranchuk A, Abdollah H, Michael
KA, Simpson C, et al. Celecoxib-induced change in atrial
electrophysiologic substrate in arthritis patients. Ann Noninvasive
Electrocardiol 2014; 1: 50 – 56.
  93. Çetin S, Mustafa G, Keskin G, Yeter E, Doğan M, Öztürk MA.
Infliximab, an anti-TNF-alpha agent, improves left atrial
abnormalities in patients with rheumatoid arthritis: Preliminary
results. Cardiovasc J Afr 2014; 25: 168 – 175.
  94. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen
JB, Svendsen JH, et al. Risk of atrial fibrillation and stroke in
rheumatoid arthritis: Danish nationwide cohort study. BMJ
2012; 344: e1257.
 95. Ungprasert P, Srivali N, Kittanamongkolchai W. Risk of
incident atrial fibrillation in patients with rheumatoid arthritis:
A systematic review and meta-analysis. Int J Rheum Dis 2017;
20: 434 – 441.
  96. Göldeli O, Dursun E, Komsuoglu B. Dispersion of ventricular
repolarization: A new marker of ventricular arrhythmias in
patients with rheumatoid arthritis. J Rheumatol 1998; 25: 447 – 
450.
  97. Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJ. Rheumatoid
arthritis and macrovascular disease. Rheumatology 2003; 42:
292 – 297.
  98. Eisen A, Arnson Y, Dovrish Z, Hadary R, Amital H. Arrhythmias
and conduction defects in rheumatological diseases: A compre-
hensive review. Semin Arthritis Rheum 2008; 39: 145 – 156.
  99. Guler H, Seyfeli E, Sahin G, Duru M, Akgul F, Saglam H, et al.
P wave dispersion in patients with rheumatoid arthritis: Its relation
with clinical and echocardiographic parameters. Rheumatol Int
2007; 27: 813 – 818.
100. Galarza-Delgado D, Azpiri-López J, Colunga-Pedraza I,
Cardiac Arrhythmias in Autoimmune Diseases
Dávila-Jiménez JA, Abundis-Márquez EE, Guillén-Lozoya AH,
et al. Left atrial dilation is increased in patients with rheumatoid
arthritis: A case-control study. Ann Rheum Dis 2018; 77: 1351 –  fibrillation and stroke in patients with psoriasis: A Danish
1352.
101. Schwemmer S, Beer P, Scholmerich J, Fleck M, Straub RH.
Cardiovascular and pupillary autonomic nervous dysfunction
in patients with rheumatoid arthritis: A cross sectional and
longitudinal study. Clin Exp Rheumatol 2006; 24: 683 – 689.
102. Guin A, Chatterjee Adhikari M, Chakraborty S, Sinhamahapatra
P, Ghosh A. Effects of disease modifying anti-rheumatic drugs
on subclinical atherosclerosis and endothelial dysfunction
which has been detected in early rheumatoid arthritis: 1-year
follow-up study. Semin Arthritis Rheum 2013; 43: 48 – 54.
103. Wen SN, Liu N, Li SN, Salim M, Yan Q, Wu XY, et al. Catheter
ablation of atrial fibrillation in patients with rheumatoid arthritis.
J Cardiol 2015; 66: 320 – 325.
104. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock
RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis.
Rheumatology (Oxford) 2014; 53: 650 – 657.
105. Aksoy H, Okutucu S, Sayin BY, Oto A. Assessment of cardiac
arrhythmias in patients with ankylosing spondylitis by signal-
averaged P wave duration and P wave dispersion. Eur Rev Med
Pharmacol Sci 2016; 20: 1123 – 1129.
106. Yildirir A, Aksoyek S, Calguneri M, Oto A, Kes S. QT dispression
as a predictor of arrhythmic events in patients with ankylosing
spondylitis. Rheumatology 2000; 39: 875 – 879.
107. Moyssakis I, Gialafos E, Vassiliou VA, Boki K, Votteas V,
Sfikakis PP, et al. Myocardial performance and aortic elasticity
are impaired in patients with ankylosing spondylitis. Scand J
Rheumatol 2009; 38: 216 – 222.
108. Bergfeldt L, Edhag O, Holm G, Norberg R. Platelet aggregating
activity in serum from patients with HLA-B27 associated
rheumatic and cardiac disorders: A possible link to the prolif-
erative vascular changes. Br Heart J 1991; 65: 184 – 187.
109. Koza Y, Taş MH, Şimşek Z, Gündoğdu F. Ventricular tacyh-
cardia in a patient with a previous history of endocarditis and
ankylosan spondylitis: A challenging case. Eurasian J Med
2016; 48: 222 – 224.
110. Toufan M, Pourafkari L, Nader ND. Left ventricular non-
compaction in a patient with ankylosing spondylitis. J Cardiovasc
Thorac Res 2016; 8: 188 – 189.
111. Miedany YEI. Spondyloarthritis with psoriasis: New insights.
J Arthritis 2012; 1: 106.
112. Ungprasert P, Srivali N, Kittanamongkolchai W. Psoriasis
and risk of incident atrial fibrillation: A systematic review and
meta-analysis. Indian J Dermatol Venereol Leprol 2016; 82:
489 – 497.
113. Upala S, Shahnawaz A, Sanguankeo A. Psoriasis increases
risk of new-onset atrial fibrillation: A systematic review and
meta-analysis of prospective observational studies. J Dermatolog
Treat 2017; 28: 406 – 410.
114. Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J,
Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation
and ischaemic stroke: A Danish nationwide cohort study. Eur
Heart J 2012; 33: 2054 – 2064.
115. Markuszeski L, Bissinger A, Janusz I, Narbutt J, Jedrzejowska
AS, Zalewska A. Heart rate and arrhythmia in patients with
psoriasis vulgaris. Arch Med Res 2007; 38: 64 – 69.
116. Simsek H, Sahin M, Akyol A, Akdag S, Ozkol HU, Gumrukcuoglu
HA, et al. Increased risk of atrial and ventricular arrhythmia in
long-lasting psoriasis patients. ScientificWorldJournal 2013;
2013: 901215.
117. Tasal A, Guvenc TS, Kul S, Bacaksiz A, Erdogan E, Sonmez O,
et al. Atrial conduction abnormalities in patients with psoriasis
vulgaris. Kardiol Pol 2015; 73: 637 – 643.
118. Lee SH, Chen YC, Chen YJ, Chang SL, Tai CT, Wongcharoen W,
et al. Tumor necrosis factor-alpha alters calcium handling and
increases arrhythmogenesis of pulmonary vein cardiomyocytes.
Life Sci 2007; 80: 1806 – 1815.
119. Musa H, Kaur K, O’Connell R, Klos M, Guerrero-Serna G,
Avula UM, et al. Inhibition of platelet-derived growth factor-AB
signaling prevents electromechanical remodeling of adult atrial
myocytes that contact myofibroblasts. Heart Rhythm 2013; 10:
1044 – 1051.
120. Mastrolonardo M, Picardi A, Alicino D, Bellomo A, Pasquini
P. Cardiovascular reactivity to experimental stress in psoriasis:
A controlled investigation. Acta Derm Venereol 2006; 86: 340 –  157: 9 – 21.
344.
121. Badokin VV, Kotelnikova GP. The heart damage in patients
with psoriatic arthritis. Ter Arkh 2004; 76: 56 – 61 (in Russian).
Circulation Journal  Vol.84, May 2020
693
122. Egeberg A, Khalid U, Gislason GH, Mallbris L, Skov L,
Hansen PR. Association between depression and risk of atrial
nationwide cohort study. Br J Dermatol 2015; 173: 471 – 479.
123. Hugh J, Van Voorhees AS, Nijhawan RI, Bagel J, Lebwohl M,
Blauvelt A, et al. From the Medical Board of the National
Psoriasis Foundation: The risk of cardiovascular disease in
individuals with psoriasis and the potential impact of current
therapies. J Am Acad Dermatol 2014; 70: 168 – 177.
124. Wu JJ, Sundaram M, Cloutier M, Gauthier-Loiselle M, Guérin
A, Singh R, et al. The risk of cardiovascular events in psoriasis
patients treated with tumor necrosis factor-α inhibitors versus
phototherapy: An observational cohort study. J Am Acad
Dermatol 2018; 79: 60 – 68.
125. Mosiewicz J, Pietrzak A, Chodorowska G, Trojnar M,
Szepietowski J, Reich K, et al. Rational for statin use in psoriatic
patients. Arch Dermatol Res 2013; 305: 467 – 472.
126. Biagi F, Raiteri A, Schiepatti A, Klersy C, Corazza GR. The
relationship between child mortality rates and prevalence of
celiac disease. J Pediatr Gastroenterol Nutr 2018; 66: 289 – 294.
127. Emilsson L, Smith JG, West J, Melander O, Ludvigsson JF.
Increased risk of atrial fibrillation in patients with coeliac disease:
A nationwide cohort study. Eur Heart J 2011; 32: 2430 – 2437.
128. Frustaci A, Cuoco L, Chimenti C, Pieroni M, Fioravanti G,
Gentiloni N, et al. Celiac disease associated with autoimmune
myocarditis. Circulation 2002; 105: 2611 – 2618.
129. Hallert C, Grant C, Grehn S, Gr.nn. C, Hult.n S, Midhagen G,
et al. Evidence of poor vitamin status in coeliac patients on a
gluten: Free diet for 10 years. Aliment Pharmacol Ther 2002; 16:
1333 – 1339.
130. Corazza GR, Frisoni M, Filipponi C, Gullo L, Poggi VM,
Gasbarrini G. Investigation of QT interval in adult coeliac
disease. BMJ 1992; 304: 1285.
131. M’Koma AE. Inflammatory bowel disease: An expanding
global health problem. Clin Med Insights Gastroenterol 2013; 6:
33 – 47.
132. Kristensen SL, Lindhardsen J, Ahlehoff O, Erichsen R,
Lamberts M, Khalid U, et al. Increased risk of atrial fibrillation
and stroke during active stages of inflammatory bowel disease:
A nationwide study. Europace 2014; 16: 477 – 484.
133. Mazlam MZ, Hodgson HJ. Interrelations between interleukin-6,
interleukin-1 beta, plasma C-reactive protein values, and in
vitro C-reactive protein generation in patients with inflammatory
bowel disease. Gut 1994; 35: 77 – 83.
134. Psychari SN, Apostolou TS, Sinos L, Hamodraka E, Liakos G,
Kremastinos DT. Relation of elevated C-reactive protein and
inter-leukin-6 levels to left atrial size and duration of episodes
in patients with atrial fibrillation. Am J Cardiol 2005; 95:
764 – 767.
135. Luckett LR, Gallucci RM. Interleukin-6 (IL-6) modulates
migration and matrix metalloproteinase function in dermal
fibroblasts from IL-6KO mice. Br J Dermatol 2007; 156: 1163 – 
1171.
136. Pattanshetty DJ, Anna K, Gajulapalli RD, Sappati-Biyyani
RR. Inflammatory bowel “cardiac” disease: Point prevalence of
atrial fibrillation in inflammatory bowel disease population.
Saudi J Gastroenterol 2015; 21: 325 – 329.
137. Efe TH, Cimen T, Ertem AG, Coskun Y, Bilgin M, Sahan HF,
et al. Atrial electromechanical properties in inflammatory bowel
disease. Echocardiography 2016; 33: 1309 – 1316.
138. Dogan Y, Soylu A, Eren GA, Poturoglu S, Dolapcioglu C,
Sonmez K, et al. Evaluation of QT and P wave dispersion and
mean platelet volume among inflammatory bowel disease patients.
Int J Med Sci 2011; 8: 540 – 546.
139. Sharma P, Makharia GK, Ahuja V, Dwivedi SN, Deepak KK.
Autonomic dysfunctions in patients with inflammatory bowel
disease in clinical remission. Dig Dis Sci 2009; 54: 853 – 861.
140. Knorr JP, Moshfeghi M, Sokoloski MC. Ciprofloxacin-induced
Q-T interval prolongation. Am J Health Syst Pharm 2008; 65:
547 – 551.
141. Riccioni G, Bucciarelli V, Di Ilio E, Scotti L, Aceto A, D’Orazio
N, et al. Recurrent atrial fibrillation in a patient with ulcerative
colitis treated with azathioprine: Case report and review of the
literature. Int J Immunopathol Pharmacol 2011; 24: 247 – 249.
142. Kim JS, Judson MA, Donnino R, Gold M, Cooper LT Jr,
Prystowsky EN, et al. Cardiac sarcoidosis. Am Heart J 2009;
143. Thomas G, Mancini J, Jourde-Chiche N, Sarlon G, Amoura Z,
Harlé JR, et al. Mortality associated with systemic lupus
erythematosus in France assessed by multiple-cause-of-death
694
analysis. Arthritis Rheumatol 2014; 66: 2503 – 2511.
144. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Mycoardial
lesions of progressive systemic sclerosis. A cause of cardiac
dysfunction. Circulation 1976; 53: 483 – 490.
145. Mitchell AR, Newton JD, Banning AP. Specific heart muscle
disorders. In: Warrell DA, Cox TM, Firth JD, Dwight J, editors.
Oxford textbook of medicine: Cardiovascular disorders. Oxford
University Press: Oxford, 2016; 276 – 280.
146. Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE,
et al. Causes and risk factors for death in systemic sclerosis: A
study from the EULAR Scleroderma Trials and Research
(EUSTAR) database. Ann Rheum Dis 2010; 69: 1809 – 1815.
147. Lynge TH, Svane J, Pedersen-Bjergaard U, Gislason G, Torp-
Pedersen C, Banner J, et al. Sudden cardiac death caused by
myocarditis in persons aged 1–49 years: A nationwide study of
14 294 deaths in Denmark. Forensic Sci Res 2019; 4: 247 – 256.
Circulation Journal  Vol.84, May 2020
GAWAŁKO M et al.
148. Australian Institute of Health and Welfare. Deaths among
people with diabetes in Australia 2009–2014. https://www.aihw.
gov.au/getmedia/c164ec7c-fc66-4991-8e53-62eba274ead4/
aihw-cvd-79.pdf.aspx?inline=true (accessed January 2, 2020).
149. Eranti A, Kerola T, Aro AL, Tikkanen JT, Rissanen HA,
Anttonen O, et al. Diabetes, glucose tolerance, and the risk of
sudden cardiac death. BMC Cardiovasc Disord 2016; 16: 51.
150. Akamizu T, Satoh T, Isozaki O, Suzuki A, Wakino S, Iburi T,
et al. Diagnostic criteria, clinical features, and incidence of
thyroid storm based on nationwide surveys. Thyroid 2012; 22:
661 – 679.
151. Mok CC, Kwok CL, Ho LY, Chan PT, Yip SF. Life expectancy,
standardized mortality ratios, and causes of death in six
rheumatic diseases in Hong Kong, China. Arthritis Rheum 2011;
63: 1182 – 1189.