Comparison of Frequency of Complex Ventricular Arrhythmias in Patients With Positive Versus Negative Anti-Ro/SSA and Connective Tissue Disease

doi:10.1016/j.amjcard.2007.04.048

The American Journal of Cardiology

Volume 100, Issue 6, 15 September 2007, Pages 1029-1034

https://doi.org/10.1016/j.amjcard.2007.04.048 Get rights and content

A previous study of electrocardiography at rest showed that anti-Ro/SSA–positive patients with connective tissue disease (CTD) frequently had corrected QT (QTc) interval prolongation. Because QTc interval prolongation is a definite risk factor for arrhythmic sudden death in the general population, a 24-hour electrocardiographic monitoring study was performed to investigate the possible relation between QTc interval prolongation and incidence of ventricular arrhythmias as a possible expression of immunomediated electric instability of the myocardium in anti-Ro/SSA–positive patients with CTD. The study population consisted of 46 patients with CTD; 26 anti-Ro/SSA–positive and 20 anti-Ro/SSA–negative (control group) patients (Sjögren's syndrome, 9 and 3 patients; systemic lupus erythematosus, 4 and 9 patients; systemic sclerosis, 2 and 4 patients; undifferentiated CTD, 8 and 1 patients; mixed CTD, 2 and 2 patients, and polymyositis/dermatomyositis, 1 and 1 patient, respectively). All patients underwent ambulatory Holter electrocardiography to obtain 24-hour monitoring of the QTc interval and ventricular arrhythmias. With respect to the control group, anti-Ro/SSA–positive patients with CTD (1) commonly showed QTc interval prolongation (46% vs 5%), and this abnormality, when present, persisted for the 24 hours (global mean 24-hour QTc interval 440.5 ± 23.4 vs 418.2 ± 13.2 ms); (2) had a higher incidence of complex ventricular arrhythmias (i.e., Lown classes 2 to 5, 50% vs 10%) also in the absence of detectable cardiac abnormalities; and (3) in patients with CTD, there is a direct relation between global mean 24-hour QTc interval and ventricular arrhythmic load independently of age and disease duration. In conclusion, anti-Ro/SSA–positive patients with CTD seemed to have a particularly high risk of developing ventricular arrhythmias. The risk appeared related mainly to abnormalities in ventricular electrophysiologic characteristics emerging in the clinical setting as QTc interval prolongation.

Section snippets

Methods

The study population consisted of 46 patients with different CTDs9, 10, 11, 12, 13, 14 allocated to 2 groups of 26 anti-Ro/SSA–positive and 20 anti-Ro/SSA–negative patients (Table 1). None of the subjects participated in the previous study of electrocardiography (ECG) at rest⁴ or used drugs potentially influencing the QTc interval, except for hydroxychloroquine (Table 1). Patients did not have electrocardiographic and/or echocardiographic abnormalities (Table 2) and/or a history consistent with

Results

In the patient group, 15 of 26 were positive for antibodies to 52- and 60-kd Ro proteins; 17 of 26, for anti–60-kd Ro; and 23 of 26, for anti–52-kd Ro. Eleven patients were also positive for anti-La/SSB antibodies. None of the controls was positive for anti-Ro/SSA and/or anti-La/SSB antibodies. Anti-Ro/SSA–positive patients showed significant prolongation of mean QTc interval during the 24-hour monitoring period with respect to anti-Ro/SSA–negative subjects (Table 3). Moreover, this difference

Discussion

The main results arising from the present study were that (1) anti-Ro/SSA–positive patients with CTD commonly showed QTc interval prolongation, and this abnormality, when present, was persistent throughout the 24-hour observation period; (2) in the same patients, a high incidence of complex ventricular arrhythmias was shown, also in the absence of detectable cardiac abnormalities of structural origin; and (3) in patients with CTD, a direct relation existed between global mean 24-hour QTc

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Long QT syndrome (LQTS) is a cardiac electrical disorder which increases the risk for malignant ventricular arrhythmias, specifically torsades de pointes (TdP). LQTS can result from a large number of etiologic factors, congenital and acquired. Mutations, mainly in potassium or sodium channel genes, drugs, and electrolyte imbalances are the most recognized causes. Structural heart disease, bradyarrhythmias, endocrine and liver diseases, nervous system injuries, starvation, hypothermia, and toxins represent other well-documented causes for acquired LQTS. Nonetheless, the above “conventional” risk factors cannot explain all cases of LQTS/TdP. In the recent years, a number of novel “nonconventional” causes of LQTS have emerged in the literature, both acquired (inflammation, autoimmunity, human immunodeficiency virus infection, male hypogonadism, heart failure with preserved ejection fraction, QT interval-prolonging foods) and genetic (polygenic mutations), with a potentially significant impact on TdP prevalence in the general population. By integrating basic and clinical research, we here provide an updated overview on this topic, also discussing the clinical implications and perspectives.
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It is well recognized that transplacental passage of maternal anti-Ro/SSA is associated with the development of the autoimmune congenital heart block,16 at least in part resulting from an inhibitory cross-reaction with L-type Ca2+ channels in the fetal cardiac conduction system.11,17 More recently, several studies demonstrated that anti-Ro/SSA–positive subjects, both newborns and adults affected or not by CTD, in 10%–60% of cases can also show heart rate–corrected QT (QTc) interval prolongation,18–27 which correlate with autoantibody levels (particularly anti-Ro/SSA-52kd)23,24,27 and occurrence of complex ventricular arrhythmias (VAs),22 including torsades de pointes (TdP).28,29 From a molecular point of view, there is strong evidence that anti-Ro/SSA-52kd can induce LQTS as a result of a cross-reactivity with the pore region of hERG, leading to an inhibition of the channel function (Table 1).
Cardiac K⁺ channelopathies account for a significant proportion of arrhythmias and sudden cardiac death (SCD) in subjects without structural heart disease. It is well recognized that genetic defects are key factors in many cases, and in practice, the term cardiac channelopathies currently coincides with inherited cardiac channelopathies. However, mounting evidence demonstrate that not only genetic alterations but also autoimmune and inflammatory factors can cause cardiac K⁺-channel dysfunction and arrhythmias in the setting of a structurally normal heart. In particular, it has been demonstrated that specific autoantibodies as well as inflammatory cytokines can modulate expression and/or function of different K⁺ channels in the heart, resulting in a disruption of the cardiac action potential and arrhythmias/sudden cardiac death. Awareness about the existence of these newly recognized forms is essential to identify and adequately manage affected patients. In the present review, we focus on autoimmune and inflammatory K⁺ channelopathies as a novel mechanism for cardiac arrhythmias and analyze the recent advancements in this topic, providing complementary basic, clinical, and population health perspectives.
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Sjogren's syndrome (SS) is a common systemic autoimmune disease, occurring mainly in women of perimenopausal period, with both local symptoms, related to exocrine glands involvement, and systemic manifestations. Growing evidence over the last few years suggests cardiovascular (CV) involvement in the setting of SS to occur much more frequently than initially thought. Increased prevalence of traditional CV risk factors, such as hypertension, hypercholesterolemia and hypertriglyceridemia has been documented among SS individuals. Several markers of endothelial dysfunction and subclinical atherosclerosis have been proposed in the context of SS, associated with disease-related clinical and laboratory features. Echocardiographic evaluation of SS patients has revealed cardiac abnormalities, including pericardial involvement, valvular defects and pulmonary hypertension, either subclinical or clinically overt. The current chapter provides a review of the literature regarding the pathophysiological aspects, prevalence and assessment of cardiac involvement among SS patients. A special reference on the pregnancy outcomes of SS females is also presented.
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The French group has not confirmed this finding in 152 pregnancies in 96 anti-SSA positive women (Costedoat-Chalumeau et al., 2004). On the other hand a QT interval prolongation has been reported also in adults positive for anti-SSA/Ro (Lazzerini et al., 2004, 2007; Bourré-Tessier et al., 2011), and recently it has been shown that anti-Ro positive sera inhibit IKr to prolong action potential duration by directly binding to the HERG channel protein inducing QTc prolongation. This topic, therefore, is still a matter of debate.
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Regular paperComparison of Frequency of Complex Ventricular Arrhythmias in Patients With Positive Versus Negative Anti-Ro/SSA and Connective Tissue Disease

Section snippets

Methods

Results

Discussion

Autoimmun Rev

Int J Cardiol

Lancet

Autoimmun Rev

Cardiac involvement in systemic autoimmune diseases

Clin Rev Allergy Immunol

Anti-Ro/SSA and La/SSB antibodies

Autoimmunity

Prolongation of the corrected QT interval in adult patients with anti-Ro/SSA-positive connective tissue diseases

Arthritis Rheum

Ventricular arrhythmias during 24-h ambulatory ECG recording: incidence, risk factors and prognosis in men with and without a history of cardiovascular disease

J Intern Med

QTc dispersion and complex ventricular arrhythmias in untreated newly presenting hypertensive patients

J Hum Hypertens

Relation of QT-interval variability to ventricular arrhythmias during percutaneous transluminal coronary angioplasty

Jpn Circ J

; European Study Group on Diagnostic Criteria for Sjogren's SyndromePreliminary criteria for the classification of Sjogren's syndrome: results of a prospective concerted action supported by the European Community

Arthritis Rheum

Regular paper
Comparison of Frequency of Complex Ventricular Arrhythmias in Patients With Positive Versus Negative Anti-Ro/SSA and Connective Tissue Disease