For Peer Review
Sinus node dysfunction as an initial presentation of adult systemic lupus erythematosus
Journal: Lupus
Manuscript ID: LUP-10-219.R1 Manuscript Type: Case Report Date Submitted by the
Author: 05-Dec-2010
Complete List of Authors: Lin, Yen Nien; China Medical University Hospital, Division of Cardiology, Department of Medicine
Liou, Ying-Ming; Department of Life Science, College of Life Science, Department of Life Science, College of Life Science, National Chung-Hsing University
Chen, Jan-Yow; China Medical University Hospital, Division of Cardiology, Department of Medicine
Chang, Kuan-Cheng; China Medical University Hospital, Division of Cardiology, Department of Medicine
Keyword: Systemic Lupus Erythematosus, Cardiovascular Disease, Anti-DNA antibodies
Abstract:
Cardiac involvement in systemic lupus erythematosus (SLE) has been well described. However, sinus node involvement with profound sinus bradycardia as an early manifestation of adult SLE has not been reported. A 27-year-old previously healthy female was admitted due to intermittent fever for 4 days. SLE was diagnosed based on clinical manifestations and laboratory data. Profound sinus bradycardia (heart rate = 41/min) with weakness were noted during hospitalization. ECG abnormalities completely resolved after a high-dose intravenous steroid infusion. Sinus node involvement with significant bradycardia is one of the possible complications in the early stage of adult SLE. Close cardiovascular monitoring and serial ECGs are suggested for early detection of this serious complication of adult SLE.
For Peer Review
Sinus node dysfunction as an initial presentation of adult systemic lupus erythematosus
Yen Nien Lin
1, Ying-Ming Liou
2, Jan-Yow Chen
1,2Kuan-Cheng Chang
11
Division of Cardiology, Department of Internal Medicine, China Medical University Hospital,
Taichung, Taiwan
2
Department of Life Science, National Chung-Hsing University, Taichung, Taiwan
Running title: Sinus node dysfunction and SLE
Correspondence to Dr. Jan-Yow Chen
Division of Cardiology, Department of Internal Medicine,
China Medical University Hospital, 2, Yuh-Der Road, North District, Taichung 40447, Taiwan.
E-mail: [email protected]
Telephone: + 886-4-22052121 ext. 2220, Fax: +886-4-22023119
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Abstract
Cardiac involvement in systemic lupus erythematosus (SLE) has been well described. However,
sinus node involvement with profound sinus bradycardia as an early manifestation of adult SLE
has not been reported. A 27-year-old previously healthy female was admitted due to intermittent
fever for 4 days. SLE was diagnosed based on clinical manifestations and laboratory data.
Profound sinus bradycardia (heart rate = 41/min) with weakness were noted during
hospitalization. ECG abnormalities completely resolved after a high-dose intravenous steroid
infusion. Sinus node involvement with significant bradycardia is one of the possible
complications in the early stage of adult SLE. Close cardiovascular monitoring and serial ECGs
are suggested for early detection of this serious complication of adult SLE.
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Introduction
Cardiac involvement in systemic lupus erythematosus (SLE) has been well documented, and
can include pericarditis, myocarditis, valvular abnormalities, coronary heart disease, and
conduction disorders
1. Conduction disorders with atrioventricular block can occur in infants born
from mother with SLE who exhibit anti-Ro/SSA antibodies. However, involvement of
conduction system with high grade atrioventricular (AV) block is extremely rare in adult SLE
patients
2,3. To the best of our knowledge, isolated sinoatrial node involvement with sinus node
dysfunction has not been previously reported as a early manifestation of SLE in adults.
Case report
A 27-year-old previously healthy female presented with a 4 day history of intermittent fever
and photosensativity, facial rash, morning stiffiness, oral ulcers, generalized myalgia, arthragia,
and hair loss. An antinuclear-antibody (ANA) titer was 1:80 with a cytoplasm pattern and 1:40
with a nucleolar pattern. Her rheumatoid factor (RF) level was 25.5 IU/ml, serum anti-native
DNA antibodies level was 620.2 U/ml, and serum immunoglobulin G level was 2100 mg/dl. The
level of complement protein C3 was 37.1 mg/dl, and the C4 level was 2.01 mg/dl. Tests for
antibodies to nuclear antigens (Sjogren's syndrome A/Ro, Sjogren's syndrome B/La, Smith),
Beta2-glycoprotein, cardiolipin, and ribosomal P were negative, but for ribonucleaprotein (RNP)
were positive. Base on the clinical presentation and laboratory data, she was diagnosed with
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SLE. On the 5th hospital day, physical examination revealed a pulse of 41 beats/min and
electrocardiogram (ECG) revealed sinus bradycardia (Figure). Echocardiopraphy revealed
normal valvular structure and systolic and diastolic function. Myocardial infarction, ischemic
heart disease, infections, hypothermia, hypothyroidism, raised intracranial pressure, high vagal
tone, electrolyte imbalance and drugs related bradycardia were excluded by clinical evidences
and laboratory data. Her abnormal ECG completely resolved 5 days after high-dose intravenous
methylprednisolone infusion, and she was maintained successfully with a low dose of oral
steroids.
Discussion
SLE, a connective tissue disease characterized by the production of the auto-antibodies and
immune complexes, can affect all organs including the heart. Cardiac involvement in SLE has
been reported, including pericarditis, myocarditis, valvular abnormalities, coronary heart disease,
and conduction system disturbances
1. Cardiac complications may develope either as incidental
findings or in association with a lupus flare. Since the symptoms may be subtle, the occurrence
and severity of the heart diseases are usually underestimated.
Conduction system disturbances in SLE are less commonly described
3. Conduction
disturbances with high grade AV block can be observed in neonatal period of infants born from
mothers with SLE. The mechanism of neonatal heart block is considered to be due to
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transplacental passage of maternal antibodies with injury of the conduction system by a direct
cytotoxic effect of anti-Ro or anti-La antibodies
4,5. However, high grade AV block is a rare
complication of adults with SLE that may occur in the setting of an acute flare-up of the disease,
as a sign of antimalarial toxicity, or as an initial manifestation
2,6,7-9. Vasculitis selectively
affecting cardiac conduction tissue without induction of overt myocarditis and vacuolar
myopathy have been implied in its pathogenesis
10. Anti-Ro, anti-La, and anti-RNP antibodies
have also been proposed as markers of cardiac involvement in adults with SLE
11,12. Pacemaker
implantation is sometimes required in patients with irreversible conduction disturbance in spite
of maximal steroid use or antimalarial withdrawal.
Sinus bradycardia may be a sign of sinus node dysfunction, ischemic heart disease,
infiltrative disorders, infections, inflammatory disease, hypothermia, hypothyroidism, raised
intracranial pressure, high vagal tone, electrolyte imbalance, and can be caused by certain
drugs.
13In the present report, the young female had no history of chest pain and no evidence of
myocardial ischemia or infarction on ECG and echocardiography. Tests of thyroid function and
serum electrolytes were within normal limits. There was also no clinical manifestations of
increased intracranial pressure, hypothermia, or infection. No history of the use of drugs that can
result in sinus bradycardia was noted. The patient’s heart rhythm was continuously monitored by
ECG monitor, and the profound sinus bradycardia was presented not only in the night, but also
during the daytime, and therefore an association with the physiologic variation of heart rate was
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excluded. In addition, no evidence of other cardiac conduction disorders such as atrioventricular
block or bundle branch block were found by ECG monitoring. Her abnormal ECG completely
resolved 5 days after high-dose intravenous methylprednisolone infusion, and no recurrence of
bradycardia occurred. Based on the above findings, short-term isolated sinus node dysfunction
presenting as profound sinus bradycardia due to SLE is highly suspected.
In the present case, we addressed the issue of bradycardia in a young female. Further
evaluation of the bradycardia is necessary because of the possibility of a serious underlying
disorder and unfavorable outcome if not treated. A detailed history, ECG follow-up, and
echocardiogrphy are essential for the differential diganosis of bradycardia. Laboratory tests for
hypothyroidism, infection, inflammatory disease and connective tissue diseases should be
performed. The tilting table test is recommended if the bradycardia occurs paroxysmally, and is
suspected to be due to vagal tone variation or orthostatic change.
14In addition, the occurrence of
episodes of bradycardia are sometimes infrequent, and therefore may not be recorded during a
routine ECG examination. Recordings over a longer period of time are frequently required for
detection and assessment of the bradycardia. Holter ECG monitoring is recommended for the
evaluation of suspected bradycardia, or further investigation of documented bradycardia in
young females.
15This can allow the severity and characteristics of the bradycardia to be further
clarified. Based on 24-hour recording data, the possibility of bradycardia due to physiologic
variation of cardiac rhythm can be excluded. Telemetry ECG monitoring is an alternative choice
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for the evaluation of bradycardia in young patients.
15It can provide a longer recording period
than Holter ECG monitoring; however, the patient must stay in a telemetry unit. A loop recorder
is also an alternative choice for non-invasive monitoring of bradycardia, and can provide a much
longer period of recording.
15Cardiac electrophysiological study is an invasive tool for the
evaluation of the sinus node and cardiac conduction system. It can assist the investigation of the
mechanism of bradycardia, and assess the results of therapy. Cardiac electrophysiological studies
are recommended when the bradycardias occur paroxysmally and cannot be evaluated by non-
invasive monitoring methods, or when a serious underlying mechanism is suspected.
16In the present case, echocardiography showed normal LV global systolic performance,
which excluded overt myocarditis. Focal myocarditis or vasculitis due to a direct cytotoxic effect
of auto-antibodies selectively affecting the sinus node without induction of diffuse myocarditis is
the suspected underlying mechanism in the present case. Magnetic resonance imaging (MRI),
single photon emission computed tomography (SPECT), and positron emission tomography
(PET) have been recently described as useful for diagnosis of myocarditis. MRI has been
reported to be a valuable tool for the evaluation and monitoring of inflammatory heart disease.
Histopathological studies have indicated that the region of contrast enhancement in MRI is
associated with active inflammation.
17With PET, a pattern of 18F-fluorodeoxyglucose (FDG)
uptake limited to cardiac structures is considered a sign of a local inflammatory process.
18The
role of SPECT myocardial perfusion imaging in patients with myocarditis is still unclear. Focal
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areas of reversible hypoperfusion on SPECT imaging has revealed concordant findings with MRI
in myocarditis.
19To the best of our knoweledge, sinus node involvement with sinus node dysfunction has not
been reported as an initial presentation of SLE in adult patients. In our reported case, we
excluded the major causes of sinus bradycardia, except for SLE. The patient's abnormal ECG
completely resolved after high-dose intravenous methylprednisolone infusion. Sinus node
involvement with significant bradycardia is one of the possible complications in the early stage
of adult SLE.
In summary, sinus node dysfunction with profound bradycardia is a possible complication
of early-stage adult SLE. We belive that the underlying mechanism is similar to AV node
involvement in adult SLE, including infiltration of fibrotic granulation tissue secondary to
inflammation, and small vessel vasculitis. A thorough cardiovascular history and periodic
electrocardiographic monitoring are suggested for early detection of this complication in the
acute phase of adult SLE.
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Reference
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Figure Legends
Figure. ECG in the early stage of SLE reveals profound sinus bradycardia (ventricular rate = 41/min).
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ECG in the early stage of SLE reveals profound sinus bradycardia (ventricular rate = 41/min).
254x190mm (96 x 96 DPI)
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Responses to the Reviewer’s Comments
Comments to the Author
Authors describe a young woman with initial features of systemic lupus, in whom
incidentally, bradycardia is recognized. They suggest an association between systemic lupus
and bradycardia, and hypothesized a dysfunction of the sinus node and possible myocarditis.
In addition, they support the association between cardiac conduction system involvement and
SLE because of the apparent resolution of bradycardia after the use of high steroid dose.
Response: Thank you for the detailed comments about this manuscript. They have proven to
be very helpful.
Responses for specific comments:
1. Bradycardia might be a symptom of sinus node dysfunction, as well as other conditions,
such as infiltrative disorders, infections, and inflammatory disease. Some diseases were
ruled-out in this case. How can we rest assure that bradycardia was due to sinus node
dysfunction and no other heart conduction system anomaly?
Response: Thanks for your comments. Sinus bradycardia may be a symptom of sinus node
dysfunction, ischemic heart disease, infiltrative disorders, infections, inflammatory disease,
hypothermia, hypothyroidism, raised intracranial pressure, electrolyte imbalance and can be
caused by certain drugs. Based on the clinical evidences and laboratory data, we have
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excluded the possibility of the above disorders except sinus node dysfunction. We have
further discussed the above issue in the paragraph of discussion. (page 4; line 3-6 and page 5;
line 10-19).
In addition, no evidence of other cardiac conduction disorders such as atrioventricular
block or bundle branch block were found by ECG monitoring. Her abnormal ECG
completely resolved 5 days after high-dose intravenous methylprednisolone infusion, and no
recurrence of bradycardia occurred. Based on the above findings, short-term isolated sinus
node dysfunction presenting as profound sinus bradycardia due to SLE is highly suspected
(page 6; line 1-5).
2. It should be discussed what is the recommended steps in the study of a young woman
with asymptomatic bradycardia, in order to point-out how other differd.ential diagnosis
can be excluded. For instance, have patient’s physicians performed a 24-h
electrocardiogram registry to discard physiologic variation of cardiac rhythm? What
could be the indication of electrophysiological mapping in this case?
Response: Thank you for your comments. We have discussed the above issues in the
paragraph of discussion. The recommended steps and potential tools for differential diagnosis
and further evaluation of the bradycardia in a young female have been listed in the
discussion. We also provided some new references (page 6; line 6-19 and page 7; line 1-8).
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3. Echocardiogram image is reported as normal, which excludes the presence of
myocarditis. So, this image is maybe not useful for the case description. Other tools
newly described for diagnosis of myocarditis in SLE patients should be talked about.
Response: Thank you for the comments. We have deleted the echocardiogram image in the
manuscript. We have also described the tools newly described, including MRI, SPECT and
PET, for diagnosis of myocarditis in SLE patients (page 7; line 9-19 and page 8; line 1-2).
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Sinus node dysfunction as an initial presentation of adult systemic lupus erythematosus
Yen Nien Lin
1, Ying-Ming Liou
2, Jan-Yow Chen
1,2Kuan-Cheng Chang
11
Division of Cardiology, Department of Internal Medicine, China Medical University Hospital,
Taichung, Taiwan
2
