Repolarization Disorders and Heart Conduction Disorders in Patients With Systemic Lupus Erythematous
Conditions: Lupus Erythematosus, Systemic, Atrioventricular Block, Sudden Death
Sponsor: Germans Trias i Pujol Hospital

 
 
 
 
 
 
 
 
Study Protocol: 
Systemic Lupus Erythematous and Heart Conduction 
Disorders 
 
 
 
NCT number: 02162992 
 
 
Latest version: Feb 22nd, 2016 
 
 
 

 
 
 
 
BACKGROUND  
The incidence of sudden death and cardiac rhythm disorders is higher in patients with autoimmune 
diseases than in the general population.1 Congenital atrioventricular block (AVB) in neonates has 
been classically associated with the transplacental passage of maternal anti-Ro antibodies.2 
Complete AVB in adult patients with connective diseases is extremely rare, although not absent. 
From 1986 to 2015, 21 cases have been described in the medical literature of complete AVB in 
patients with connective diseases, 42% of whom were patients diagnosed with systemic lupus 
erythematosus. Of the total, 76% were positive for anti-Ro / SSA.1 antibodies, (PubMed® 1989-
2015, keywords: atrioventricular block, autoimmune disease, systemic lupus erythematosus, SSA / 
anti-Ro antibodies). 
Anti-Ro antibodies can be positive in several systemic diseases such as systemic lupus 
erythematosus, Sjögren's syndrome, polymyositis, dermatomyositis, systemic sclerosis and in 3% of 
the general population.1 The pathogenesis of conductive defects in connective diseases in adults has 
been classically associated with infiltration of the conduction tissue by fibrosis or granulation tissue 
in some cases, with occlusion of the artery of the atrioventricular nodule by vasculitis in others, and 
with sequelae of myocarditis in others.1,3,4 
The pathogenesis of cardiac conduction disorders in patients positive for anti-Ro / SSA antibodies is 
not clearly elucidated and there are conflicting data in this regard.3,4 Recent experimental studies 
have allowed to elaborate a new theory in which there would be a unique pathogenic sequence based 
on the interaction of anti-Ro/SSA antibodies with the calcium channels of the cardiomyocyte surface. 
Anti-Ro antibodies would interact with calcium channels by molecular mimicry causing reversible 
inhibition of calcium currents at first and, at a later stage, internalization of these channels which 
would induce apoptosis and cell death. This would lead to a process of local inflammation that would 
sustainably create fibrosis of the conductive tissue. A possible explanation of the infrequent 
involvement of the adult heart compared to the neonate would be the greater dependence of the 
transarcolemmic calcium passage, through L-calcium channels, due to the underdevelopment of the 
neonatal sarcoplasmic reticulum.1,5 
In June 2013, our group described the first case of complete BAV in a young patient with anti-
Ro/SSA positive antibodies in whom an electrophysiological study is available and therefore the 
level of conduction block could be located, being this distal to the atrio-ventricular node. Together 

 
 
 
with the presence of the left bundle branch block, these data suggested a specific involvement of 
Purkinje fibers.6 
The only information available on this subject is based on isolated cases like ours. There are no 
publications on the subsequent follow-up of these patients, nor recommendations on the therapeutic 
attitude or cardiologic check-up in patients with connective diseases and anti-Ro/SSA antibodies. 
And there is not established indication for anti-Ro/SSA antibodies testing in young patients without 
known autoimmune pathology who have been diagnosed with an AVB. 
Therefore, we carried out a first retrospective observational study in which the data of all patients 
implanted with a pacemaker in our center from 1987 to 2011 were reviewed. The study group 
included young adults between 18 and 50 years of age at the time of pacemaker implantation due to 
AVB of unknown origin and without structural heart disease. A total of 19 patients, with a mean 
implant age of 36 ± 10 years, was studied with clinical evaluation and an immunological study 
including antinuclear antibodies (ANA), extractable nuclear antigens (ENA) and anti-Ro/SSA. Six 
patients (31.6%) presented markers of immune disease, of whom 2 patients (10.5%) showed 
antibodies against specificities SS-A / Ro.14 
The next step is to conduct a prospective analysis study of adult patients with autoimmune disease 
and presence of anti-SS-A/Ro antibodies and compare them with negative anti-SS-A/Ro patients to 
determine the existence of conduction disorders or other disorders by electrocardiographic non-
invasive methods. 
Currently available data on the effect of these autoantibodies on adult cardiac tissue are 
controversial. Logar and collaborators conducted a cohort study of 36 patients with SLE and 31 
healthy controls and found that anti-Ro/SSA antibodies were associated with myocarditis and 
conduction defects in adults with SLE.8 In patients with polymyositis, Behan and colleagues reported 
an association between the presence of anti-Ro antibodies and heart damage.7 In addition, Lazzerini 
et al. described a high prevalence of the prolonged QTc interval in patients with connective tissue 
diseases that were anti-Ro/SSA positive.13 On the other hand, Gordon et al., studied 19 mothers of 
children with neonatal lupus and 111 patients with SLE, but a relationship between the presence of 
anti-Ro/SSA and cardiac conduction defects could not be stablished.15 
 
 
 

 
 
 
REFERENCES 
1. Lazzerini PE, Capecchi PL, Laghi-Pasini F. Anti-Ro/SSA antibodies and cardiac arrhythmias in the adult: facts 
and hypotheses. Scand J Immunol. 2010; 72: 213-272. 
2. Chameides L, Truex RC, Vetter V, Rashkind WJ, Galioto FM Jr, Noonan JA. Association of maternal systemic 
lupus erythematosus with congenital complete heart block. N Engl J Med.1977; 297:1204-7. 
3. Seferović PM, Ritić AD, Maksimović R, et al. Cardiac arrhythmias and conduction disturbances in autoinmune 
rheumatic diseases. Rheumatology. 2006;45:39-42. 
4. Edwards CS, Mootoo R, Bhanji A. High grade heart block in association with SLE. Ann Rheum Dis. 2004; 
63:606. 
5. Costedoat-Chalumeau N, Georgin-la-Vialle S, Amoura Z, Piette J-C. Anti-SSA/Ro and anti-SSB/La antibody-
mediated congenital heart block. Lupus. 2005;14: 660-664. 
6. Santos-Pardo I, Martínez-Morillo M, Villuendas R, Bayes-Genis A. Anti-Ro Antibodies and Reversible 
Atrioventricular Block. N Engl J Med. 2013; 368:2335-7. 
7. Behan WMA, Behan PO, Gairns J. Cardiac damage in polymyositis associated with antibodies to tissue 
ribonucleoproteins. Br Heart J 1987;57:176–80.  
8. Logar D, Kveder T, Rozman B, Dobovisek J. Possible association between anti-Ro antibodies and myocarditis 
or cardiac conduction defects in adults with systemic lupus erythematosus. Ann Rheum Dis 1990;9:627–9. 
9. O’Neill TW, Mahmoud A, Tooke A, Thomas RD, Maddison PJ. Is there a relationship between subclinical 
myocardial abnormalities, conduction defects and Ro⁄La antibodies in adults with systemic lupus 
erythematosus? Clin Exp Rheumatol 1993;11:409–12.  
10.  Lodde BM, Sankar V, Kok MR, Leakan RA, Tak PP, Pillemer SR. Adult heart block is associated with disease 
activity in primary Sjogren’s syndrome. Scand J Rheumatol 2005;34:383–6.  
11. Costa M, Silva MB, Silva JA, Silva JA, Skare TL. Anti Ro, anti La, anti RNP antibodies and 
electrocardiogram’s PR interval in adult patients with systemic lupus erythematosus. Acta Reumatol Port 
2008;33:173–5.  
12. Lazzerini PE, Capecchi PL, Guideri F, Acampa M, Galeazzi M, Laghi Pasini F. Connective tissue diseases and 
cardiac rhythm disorders: an overview. Autoimmun Rev. 2006 May;5(5):306-13.  
13. Lazzerini PE, Capecchi PL, Acampa M, Morozzi G, Bellisai F, Bacarelli MR, Dragoni S, Fineschi I, Simpatico 
A, Galeazzi M, Laghi-Pasini F. Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of 
antibody level and specificity. Arthritis Care Res (Hoboken). 2011 Oct;63(10):1463-70. 
14. R.  illuendas, A. Oliv ,  . Junc , I. Salvador, M. Mart ne -Morillo, I. Santos-Pardo, D. Pereferrer, E. Zamora1, 
A. Bayes-Genis. Autoimmunity and Atrioventricular Block of Unknown Etiology in Adults: the Role of Anti-
Ro/SSA antibodies. J Am Coll Cardiol 2014 Apr 8;63(13):133. 
15. Gordon PA, Rosenthal E, Khamashta MA, Hughes GR. Absence of conduction defects in the 
electrocardiograms of mothers with children with congenital heart block. J Rheumatol 2001;28:366–9. 
 
 

 
 
 
HYPOTHESIS 
- 
Patients with SLE positive for the antiRo/SSA autoantibody have a higher incidence of 
cardiac conduction disorders than those with negativity. 
- 
Patients with SLE and antiRo/SSA have a higher incidence of syncopal episodes than patients 
with negativity. 
- 
 Patients with SLE and anti-Ro/SSA positive autoantibody have a longer QT and higher 
incidence of ventricular tachyarrhythmias than patients with SLE and negative test. 
 
OBJECTIVES 
- 
To describe the incidence of cardiac conduction disorders in patients with SLE based on their 
serological profile. 
- 
If the association is confirmed, determine if the higher incidence of conduction disorders is 
clinically translated into a greater number of clinical events. 
- 
To confirm that the presence of the anti-RO/SSA autoantibody in circulating blood in patients 
with SLE is associated with a lengthening of the QT interval with respect to subjects with 
negativity for the autoantibody. 
 
SECONDARY OBJECTIVES 
- To determine if the positivity for subunit 60 of the Ro autoantibody is associated with cardiac 
conduction disorders or alteration of cardiac repolarization by lengthening the QT interval. 
 
METHODOLOGY 
Design 
- 
It is a cross-sectional study of which an observational analysis will be carried out. 
Subjects 

 
 
 
- 
Target population: Patients with SLE visited in the Rheumatology service of an hospital in 
Catalonia. 
- 
Accessible population: Patients with SLE visited in the Rheumatology service of the 
Germans Trias i Pujol University Hospital in Badalona. 
 
Criteria for selecting subjects: 
- 
 Inclusion criteria:  
o Diagnosis of SLE according to the 1997 diagnostic criteria (see annex 2). 
- 
 Exclusion criteria: 
o Presence of cardiac structural disease: 
  Ischemic heart disease 
 Congenital or acquired structural heart disease (hypertrophic cardiomyopathy, 
idiopathic dilated cardiomyopathy, valvular heart disease). 
 History of cardiac surgery or cardiac ablation procedures. 
 History of other pathological processes that could affect cardiac conduction: 
 Steinert's disease 
 Lyme disease 
 Chagas disease  
 Hypothyroidism 
Recruitment 
The selection of patients and controls will be carried out by a consecutive sampling of the patients 
visited in the Rheumatology office. 
 
 

 
 
 
MEASUREMENTS  
 Main variables: 
- 
Study of cardiac conduction disorders by analyzing the resting electrocardiogram and 24-hour 
Holter. 
Descriptive variables: 
- 
Collection of the general pathological history of the patients, with targeted interrogation of 
the rheumatic and cardiac involvement and registration of the usual medication. 
- 
Weight and height and physical examination. 
- 
ECG at rest: analysis of the base rhythm, PR duration, QRS and QT intervals. Presence of 
intraventricular conduction disorders. Presence of ectopic beats. 
- 
24-hour Holter recordings: presence and number of ventricular ectopic beats, classification of 
episodes according to Lown's criteria. Presence of significant pauses (RR intervals> 2000 
msec). QTc interval measurement. Autonomic dysfunction parameters: time domain 
parameters, such as the average of the RR intervals, the standard deviation of all normal RR 
intervals (SDNN), the root of the difference of successive means between the normal adjacent 
RR intervals (RMSSD), and the percentage of adjacent intervals with more than 50 ms 
(PNN50). 
- 
Basic transthoracic echocardiogram: with analysis of ventricular diameters, systolic and 
diastolic function, valvular morphology and functionalism, determination of systolic 
pulmonary pressure, study of pericardial involvement and screening of acquired or congenital 
structural heart disease. 
- 
Serological analysis: immunological profile, organic involvement by lupus, activity indices 
and chronic lupus damage. (see annex 3) 
Confusion factors: 
- 
Concomitant mediation with effect on AV conduction function. 
- 
Immune profile. 

 
 
 
STATISTICAL PLAN 
With the hypothesis of demonstrating a correlation greater than 0.5 or greater difference in the 
control to 20%, a sample size has been calculated around 57 patients and 29 controls (for statistical 
power of 0.8, confidence interval and a ratio of 0.95 cases / controls 0.5). Since the aim of the study 
was to perform an analysis adjusted for confounders, and there are at least four factors (taking 
concomitant medication with effect on AV conduction, advanced age, sex and immunological 
profile) it has decided to predetermine the sample size of 100 cases and 50 controls. 
First there will be a description of the sample, obtaining the average and standard deviation positive 
and negative for each of the variables in the group of 52 Ro-positive and the negative Ro52 as well 
as the percentage of the same. We will calculate the differences concerning the distribution of 
variables between groups using the Student t test and chi square. The analysis of association between 
these variables is made by linear regression analysis in the presence or absence of other factors, from 
which it obtained the odds ratio (odds ratio 
- 
The obtained variables will be compared using Student's t-test for quantitative data and 
Fisher's and chi-square tests for qualitative data.  
- 
Pearson correlation coefficient will be used to analyze the correlation between two variables. 
- 
Calculations will be made using SPSS statistics software.  
- 
The significance level adopted will be 5%. 
 
 
 
 
 
 
 
 

 
 
 
INFORMED CONSENT FORM 
 
CARDIC CONDUCTION  DISORDERS 
IN PATIENTS WITH SYSTEMIC LUPUS ERITEMATOSUS 
 
 
INFORMED CONSENT FOR PATIENTS 
- 
 
Mr/Ms 
………………………………………………………………………………………………………………………………….., with 
NIC……………………………………………………………………………….., I manifest that I have been informed by  
Dr. 
. ………………………………………………………………………………………………………………………………… about 
the nature of the study for which a series of tests and complementary tests will be carried out to determine: 
The cardic conduction  disorders in patients with systemic lupus eritematosus 
 
I understand that the purpose of the tests is to help my doctor in the diagnosis of the disease and investigate the 
electrocardiographic alterations that it produces. Some of these complementary tests are not part of the usual clinical practice in 
patients with systemic lupus erythematosus (SLE). 
 
I consider that the information has been given to me in an understandable way and my questions have been answered, so I have 
voluntarily decided to give my authorization. I understand that participation is voluntary, and that refusal to participate will not 
negatively influence the medical care received. Likewise, I have been informed as a patient that participation in this study 
includes additional visits. 
 
I further understand that the data obtained may also be used for research in the knowledge of these diseases and that, although this 
information may not provide useful information for me at this time, it may be in the future. 
 
For its side, the medical team undertakes to keep the anonymity of the data obtained, in compliance with Spanish Organic Law 
15/99 on the Protection of Personal Data. 
 
 
 
In Badalona at……………………………. Of ……………………………. Of ……………………. 
 
 
 
 
 
Signature of the investigator  
 
 
Signature of the patient