Arrhythmias and Conduction Defects in Rheumatological Diseases—A Comprehensive Review

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Arrhythmias and Conduction Defects in Rheumatological Diseases—A Comprehensive Review Alon Eisen, MD, Yoav Arnson, MD, Zamir Dovrish, MD, Ruthy Hadary, MD, and Howard Amital, MD, MHA

Objectives: To review the clinical aspects of cardiac arrhythmias and conduction disturbances in several common and less encountered adult rheumatic diseases and to underline the importance of prompt diagnosis and management in these patients. Methods: The PubMed database was searched for articles published between the years 1960 and 2008 for keywords referring to autoimmune diseases. All relevant English-written articles were reviewed. Most were uncontrolled series and case reports, due to the lack of prospective studies and randomized trials. Results: Rheumatologic conditions may affect the cardiovascular system and increase morbidity and mortality. Rhythm and conduction defects are usually mild but may be life-threatening; in certain diseases, such as in systemic lupus erythematosus they may resolve following therapy with corticosteroids. Conduction defects occur frequently in patients with spondyloarthropathies and in those with various forms of vasculitis. Enhanced variation of the QT interval may be a sensitive marker of a higher arrythmogenic tendency in patients with autoimmune conditions. Conclusions: It is important to identify patients at high risk for cardiac arrhythmias. Treating such patients with arrhythmias should not differ fundamentally from other patients. Nevertheless, appropriate clinical attention and judgment should be applied to exclude the possibility that arrhythmias reflect uncontrolled myocardial inflammation. © 2009 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 39:145-156 Keywords: arrhythmia, heart blocks, autoimmunity, spondyloarthropathy, systemic lupus erythematosus, rheumatoid arthritis

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heumatologic conditions often involve the cardiovascular system and may carry implications on morbidity and mortality. Cardiac involvement in connective tissue disease (CTD) can present as arrhythmias and conduction defects regardless of preexisting structural heart disease. Arrhythmias often appear during the course of the disease, although they may present as the first manifestation of the disease. The arryhthmogenic mechanism is often unclear; however it is most commonly related to myocardial inflammation and fibrosis within the conduction system. In this review we evaluated the clinical aspects of cardiac arrhythmias and conduction defects in several adult rheumatologic diseases and emphasize the importance of

Department of Medicine D, Meir Medical Center, Kefar-Saba, Israel, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Address reprint requests to Howard Amital, MD, MHA, Head of Internal Ward D, Meir Medical Center, Tscernichovsky 59, Kefar Saba, 44281 Israel. E-mail: [email protected].

0049-0172/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2008.05.001

prompt diagnosis and management of these conditions (Table 1). METHODS A Medline search utilizing the index terms “rheumatologic diseases,” “arrhythmia,” “conduction defect,” “rheumatoid arthritis,” “systemic lupus erythematosus,” “electrocardiogram,” “systemic sclerosis,” “polymyositis,” “dermatomyositis,” “mixed connective tissue disease,” “Sjogren’s syndrome,” “HLA B27,” “Takayasu’s arteritis,” “Kawasaki,” “Behcet’s disease (BD),” “Wegener’s granulomatosis,” “sarcoidosis,” “anti-Ro and anti-La antibodies,” and “antiphospholipid syndrome” was used. The English language articles/abstracts from 1960 to 2008 were reviewed. References noted in relevant articles were also assessed. The list of articles reviewed herein is not exhaustive, with preference given, where possible, to studies and surveys over case reports as well as the most recent literature reflecting developments on the subject. 145

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Table 1 Summary of Common Arrhythmias and Conduction Defects in Rheumatological Diseases Disease Rheumatoid arthritis Systemic lupus erythematosus

Arrhythmias

Polymyositis and dermatomyositis Mixed connective tissue disease

Sinus tachycardia; atrial premature contractions; atrial fibrillation Ventricular arrhythmias: premature ventricular contractions; ventricular tachycardia Ventricular tachycardia (rare) Sinus tachycardia

Sjogren’s syndrome

Ventricular arrhythmias (not clear)

HLA B-27 spondyloarthropathies

Sarcoidosis Anti-Ro and anti-La antibodies

Ventricular premature beats; supraventricular extrasystoles Ventricular arrhythmias (rare) Ventricular tachycardia (rare) Ventricular arrhythmias Supraventricular arrhythmias: atrial tachycardia, fibrillation, flutter Ventricular tachycardia Complex ventricular arrhythmias

Antiphospholipid syndrome

Ventricular arrhythmias (rare)

Systemic sclerosis

Takayasu arteritis Kawasaki disease Behcet’s disease Wegener’s granulomatosis

Conduction Defects AV blocks; RBBB AV blocks; Intraventricular blocks; Sick sinus syndrome LBBB; RBBB; First-degree AV block Left anterior hemiblock; RBBB Intraventricular blocks; complete AV block First-degree AV block; complete AV block AV blocks; intraventricular blocks Complete Complete Complete Complete

AV AV AV AV

block block block block

(rare) (rare) (rare) (rare)

Intraventricular blocks; AV blocks Complete AV block; first- and second-degree AV block. Complete AV block (rare)

AV, atrioventricular; RBBB, right bundle branch block; LBBB, left bundle branch block.

RESULTS Rheumatoid Arthritis Rheumatoid arthritis (RA) is the most common form of chronic inflammatory polyarthritis. RA patients often suffer from extra-articular manifestations involving the cardiovascular system; pericardial involvement may occur in up to 50% of the patients. Wisowska and coworkers (1) examined 24-hour electrocardiographic recordings of 70 RA patients. Rhythm disorders were found to occur at similar rates in RA patients with and without rheumatoid nodules as in healthy controls. Similar results were also obtained by Tlustochowicz and coworkers (2), who investigated 70 RA patients. In their study, they observed that arrhythmias were not correlated with arthritis progression, treatment administered, familial occurrence of arthritis, extra-articular involvement, presence of rheumatoid factor, or disease stage. In contrast, Goldeli and coworkers (3) found that the prevalence of premature ventricular contractions (PVCs) was higher in 42 RA patients compared with controls, with a correlation between complex PVCs and dispersion variables. Increased QT dispersion in RA patients has also been demonstrated by other authors as well (4,5). Heart rate variability is a useful tool detecting the sympathetic-parasympathetic balance of the autonomic nervous system. Reduction in heart rate variability is considered to be an expression of cardiovascular autonomic dysfunction. Heart rate variability has been studied in RA patients. Parnes and coworkers (6) observed a significant correlation between RA activity and heart rate variability.

They studied 78 RA patients with diverse degrees of disease activity during a follow-up period of 2 to 4 years. A clear correlation was observed between RA activity and cardiac rhythm variability as measured by electrocardiographic (ECG) recordings. The decrease in cardiac rate variability was concordant with high disease activity and with an increased risk of sudden cardiac death and acute myocardial infarction within the follow-up period (6). However, the statistical power of their study was limited due to the small number of patients included. Evrengul and coworkers (7) also suggested an increase in sympathetic control of the heart rate in 42 RA patients. An inverse relation between heart rate variability and disease activity was also recently confirmed by Anichkov and coworkers (8). In their study, heart rate variability correlated with leukocyte count, disease duration, and smoking. Schwemmer and coworkers (9) performed a cross-sectional longitudinal study in RA patients to evaluate the presence of cardiovascular autonomic dysfunction using autonomic cardiovascular standardized tests. The authors found a high prevalence of cardiovascular autonomic dysfunction in RA patients, and the presence of significantly more severe autonomic dysfunction in 4 patients that died. They concluded that increased sympathetic activity could play a key role in the development of ventricular tachyarrhythmias in RA patients. All degrees of atrioventricular (AV) block and particularly the occurrence of complete AV block has been described in RA patients (10-12). AV block is more common in patients with subcutaneous nodules and either

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can be sudden or may progress from minor conduction abnormalities. In autopsy studies, the characteristic histopathological finding is a rheumatoid granuloma located at the AV node or within the bundle of His, or in proximity to these structures (12,13). AV blocks in RA patients do not respond to anti-inflammatory therapy or to immunosuppressive treatment. Villecco and coworkers (11) described right bundle branch block (RBBB) in 35% of 60 patients with RA. In this study, the prevalence of autoantibodies to cardiac conduction tissue, antinuclear antigens, and smooth muscle cells, as measured by indirect immunofluorescence, was higher in RA patients compared with healthy controls. Furthermore, the prevalence of antibodies to cardiac conduction tissue in RA patients was significantly higher in patients with RBBB as compared with RA patients without RBBB, but was not related to the duration of disease. It should be mentioned that RA patients have a significantly higher risk of sudden cardiac death when compared with non-RA subjects. In a recent study conducted by Maradit-Kremers and coworkers (14), the estimated cumulative incidence of sudden death during 3 decades of follow-up was 7% in a RA cohort as compared with 4% in a non-RA cohort (P ⫽ 0.052). Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of immune complexes and antinuclear antibodies. Heart conduction defects in SLE usually develop with coexisting myocarditis, pericarditis, or coronary heart disease. Conduction disturbances and arrhythmias occur in about 10% of patients with SLE (15-17). Cardiac conduction defects occur in about 5% of all SLE patients and include all degrees of AV block, intraventricular conduction defects such as bundle branch blocks, and sick sinus syndrome. In adults, complete heart block is a rare manifestation of SLE and has been described only as case reports (18-20). Conduction defects in SLE are seen either as incidental findings or during disease flares (20). In general, conduction defects have been observed more frequently in young women with SLE as the disease progresses. However, Maier and coworkers (18) described a patient whose SLE presented with complete AV block. Conduction abnormalities in SLE have been attributed to several causes: it may result from myocarditis or pericarditis or can develop as a consequence of coronary ischemia secondary to vasculitis and atherosclerotic involvement (21). Collagen deposits may accumulate within the AV node, resulting in focal degeneration and fibrosis of the conduction system (22-24). The most common cardiac arrhythmias described in SLE are sinus tachycardia, atrial premature contractions, and atrial fibrillation (AF), while ventricular arrhythmias are rarely seen (16,17).

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Guzman and coworkers (25) investigated the relation between heart rate and disease activity in 39 SLE patients and found that 50% of them had sinus tachycardia. This condition was strongly correlated with disease activity, as measured by erythrocyte sedimentation rate, leukocyte and erythrocyte counts, C3 and C4 concentrations, and anti-double-stranded DNA antibody (anti-dsDNA) titers. Similar results were obtained in 137 SLE patients by Hejtmancik and coworkers (16). Supraventricular arrhythmias usually resolve spontaneously after commencing immunosuppressive treatment. The underlying pathophysiology of supraventricular arrhythmias in SLE is not clear. Whether it is related to myocardial fibrosis that induces reentry cycles or related to myocarditis or pericarditis is unknown (26). Several studies suggest that a significant number of SLE patients have sympathetic dysautonomia manifested as abnormal heart rate variability (27,28). Cardoso and coworkers (29) have investigated 140 SLE patients and found QT interval prolongation compared with healthy controls. Systemic Sclerosis Systemic sclerosis (SSc) is a CTD of unknown etiology affecting the skin and visceral organs. Vascular abnormalities, particularly of the microvasculature system, are important features of SSc (30,31). An abnormal ECG is present in 25-75% of patients with SSc and is an independent predictor of mortality (32,33). In a prospective ECG study involving 50 patients with progressive SSc, 32% had resting ECG abnormalities. The most common abnormality was left bundle branch block (LBBB) (16%), followed by first-degree AV block (8%) (32). RBBB is also common (3-6%) as are nonspecific intraventricular conduction defects. Surprisingly, second- and third-degree AV blocks are uncommon (⬍2%) (31). Ambulatory 24-hour ECG monitoring also exhibited a higher rate of conduction defects (32). Intracardiac electrophysiologic data obtained from 20 SSc patients detected functional abnormalities of the sinoatrial (SA) node, atria, and AV node in 7, 9, and 10 patients, respectively (32). Of the 20 patients who had electrophysiologic studies only 6 had entirely normal findings. Rokas and coworkers (34) investigated 30 SSc patients undergoing electrophysiological studies and demonstrated a high prevalence of conduction abnormalities (70%), with 14 patients having more than 1 electrophysiologic defect (34). Autopsy and endomyocardial biopsies reveal the presence of patchy myocardial fibrosis in SSc that involve the cardiac conduction system (35). Whether fibrosis is solely responsible for the pathophysiology of these conduction defects is not certain. Ridolfi and coworkers (35) investigated the conduction system of 35 patients with progressive SSc and concluded that sinus node and bundle system fibrosis is not significantly correlated with ECG abnor-

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malities. They concluded that the conduction system appears to be relatively spared from the myocardial changes of progressive SSc and that the high incidence of conduction disturbances in this condition may be a consequence of damaged myocardium. In contrast, Roberts and coworkers (32) reported that AV node fibrosis is related to first-degree AV block. Furthermore, Tzelepis and coworkers (36) recently reported an association between the presence of cardiac arrhythmias and conduction disturbances and myocardial fibrosis in 36 SSc patients. Several other pathophysiological mechanisms have been suggested; Volta and coworkers (37) reported that 25% of patients with progressive SSc have cardiac conduction tissue antibodies as demonstrated by indirect immunofluorescence. However, no significant correlation was found between the presence of these antibodies and conduction abnormalities in the 32 SSc patients that were included in this study. Ventricular arrhythmias are also common in SSc patients; PVCs, often appearing as couplets or multifocal beats, were the most common form of arrhythmia detectable in 67% of SSc patients. Furthermore, ventricular ectopy was strongly correlated by both univariate and multivariate analysis with overall mortality and with sudden cardiac death (SCD) during a mean follow-up of 13 months (33). Bulkley and coworkers (30) have also demonstrated a high rate of SCD in progressive SSc patients. However, Lee and coworkers (38) reported a 24% mortality rate during a 6-year period in 275 SSc patients, but only 5 of these 61 deaths were attributed to cardiac causes and none of these events were SCD. In a comprehensive study conducted over 30 years, only 18 cases (5%) of SCD were reported within a study group of 1258 SSc patients (39). Interestingly, a subgroup of 25 patients who had cardiac and skeletal myopathy also had sustained ventricular tachycardia (VT) (24%) and SCD (48%). Besides this report, other risk factors related to SCD in SSc patients were not clearly delineated. Ventricular late potentials (40), heart rate variability (41), increased QT dispersion (42,43), and concomitant anti- and pro-arrhythmogenic drugs (44) have all been associated with SCD. The prognostic significance of these factors requires further investigation. The mechanisms underlying ventricular arrhythmias in SSc are complex and possibly related to diffuse myocardial fibrosis, decreased coronary perfusion, and dynamic vasospasm, which promote reentry cycles, automaticity, and triggered activity (45,46). Premature atrial contraction, atrial flutter, AF, and supraventricular tachycardia (SVT) are also commonly recorded on ambulatory ECG studies (33). It is not clear whether arrhythmias and conduction defects in SSc are associated with clinical variants of scleroderma (limited or diffused SSc), or with other signs and symptoms of the disease (47).

Arrhythmias and autoimmunity

Polymyositis and Dermatomyositis Polymyositis (PM) and dermatomyositis (DM) are characterized by progressive weakness of the proximal skeletal muscles and both conditions may affect the heart. Cardiac involvement is considered to be the third leading cause of death in these diseases, following sepsis and malignancy (48). ECG abnormalities were found in 25 of 77 (32%) PM patients (33%) (49). These abnormalities included mainly left anterior hemiblock (13%) and RBBB (9%). No association was observed between these defects and clinical activity of PM, neither to the severity or duration of disease nor to the extent of creatine kinase level elevation. Interestingly, most of these abnormalities occurred in the absence of cardiac symptoms, perhaps indicating subclinical heart involvement. AV blocks and sick sinus syndrome have been reported less frequently than intraventricular conduction defects (50-52). A small number of case studies reported heart blocks presenting as the first manifestation of PM (50). An autopsy study of 16 patients with DM and PM who had conduction defects found that myositis and fibrosis were predominant within the conduction system (51). Tachyarrhythmias are uncommon in PM and DM (49). Adler and coworkers (53) reported a 47-year-old man who suffered from recurrent episodes of exertional syncope due to episodes of telemetry recorded VT. Further investigation revealed the clinical diagnosis of DM complicated by cardiac muscle involvement. Treatment with sotalol, prednisolone, and azathioprine led to an 18month syncope-free period. QT prolongation has been observed in a juvenile DM patient that was normalized by treating the underlying disease (54). Mixed Connective Tissue Disease Mixed connective tissue disease is characterized by clinical signs and symptoms resembling SLE, SSc, PM, and RA. Cardiovascular manifestations are common and rhythm abnormalities appear in approximately 50% of the patients (55). Most of these abnormalities are minor such as left anterior hemiblock and nonsignificant intraventricular defects. Some case studies have reported complete heart block in this disease. In 1 case a slowly progressive fibrotic disease of the cardiac conduction fibers requiring insertion of a permanent pacemaker was described (56). In another report, transient complete AV block probably resulting from acute myocarditis was identified (57). After 3 days of prednisolone therapy the heart block resolved. Alpert and coworkers (55) examined 38 mixed connective tissue disease patients in the largest case series study published. No rhythm abnormalities or conduction defects were reported in this cohort. Palpitations were present in 15% of the patients and tachycardia was common as well.

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Sjogren’s Syndrome Sjogren’s syndrome (SS) is an autoimmune disease affecting mainly the exocrine glands. The majority of patients have symptoms related to diminished lacrimal and salivary gland function. Systemic manifestations are seen in one-third of the patients with SS, whereas cardiac involvement in SS is not common and is usually smoldering. The prevalence of arrhythmias and conduction defects in SS is not clear. The adult AV node is generally thought to be resistant to the damaging effect of anti-Ro (SSA) and anti-La (SSB) autoantibodies. However, anecdotal case reports suggest that heart block developing in adult SS patients may be associated with such concurrent autoantibodies (58). First-degree AV block as well as complete heart block have been described in SS patients (59). Lodde and coworkers (59) found an association between disease activity, the presence of anti-La (SSB) antibodies, and the occurrence of first-degree AV block in adults with primary SS. Whether arrhythmias are more common in SS patients deserves further investigation. Yet, an association exists between the disease and several risk factors for ventricular arrhythmias. QT interval prolongation was reported among RA patients with secondary SS as compared with QT interval in RA patients without SS and healthy controls (60). Autonomic dysfunction is often encountered as well in SS patients; autonomic cardiovascular dysfunction assessed by an impaired response of blood pressure to sustained hand grip, Valsalva maneuver, and heart rate response to deep breathing was recorded in 68% of SS patients compared with only 13% in controls. Similarly, impaired baroreflex sensitivity was observed in a large cohort of patients with SS (61,62). HLA-B27-Associated Spondyloarthropathies Rheumatoid factor-negative spondyloarthropathies include ankylosing spondylitis (AS), psoriatic arthritis, inflammatory bowel disease associated arthritis, and reactive arthritis. Conduction abnormalities are more common in men and approximately 20% of men with permanent pacemakers have the HLA B27 gene (63,64). The pathophysiology involves an inflammatory process and myocardial fibrosis as part of the aortic root disease that is characteristic in this group of diseases (63,65). It is estimated that one-third of AS patients experience conduction abnormalities. AV block is the most common conduction defect in HLA B27 gene carriers (63-65). The level of the block is usually at the AV node rather than within the fascicles (66,67). This is in contrast with the acquired form of complete heart block where in 80% of the cases the dysfunction is located within or below the bundle of His (68). AV blocks in HLA B27 associated spondyloarthropathies usually are of an intermittent nature, suggesting an inflammatory process rather than permanent fibrosis (65). AV conduction disturbances also occur in

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reactive arthritis, usually in longstanding disease (69), but may occur early in the disease course (70). Bundle branch blocks as well as intraventricular blocks also have been reported as well (65). Bradycardia due to sinus node dysfunction has been seen on invasive electrophysiologic testing (71). Yildirir and coworkers (72) found that QT dispersion, which is the variation in duration of the QT interval in the different ECG leads, is significantly greater in AS patients than in normal subjects. In this study, AS patients displayed a significantly higher frequency of both PVCs and supraventricular extrasystoles as compared with control subjects, which correlated with QT dispersion. These findings suggest that an arrythmogenic potential exists in these patients. Nevertheless, this issue requires further evaluation. Takayasu’s Arteritis Takayasu’s arteritis (TA) is an idiopathic large-vessel vasculitis of young women affecting primarily the aorta and its major branches. Very few studies examined the prevalence of arrhythmias and conduction defects in TA. Siburian and coworkers (73) examined 78 women with TA by 24-hour electrocardiographic monitoring. They demonstrated that complex ventricular arrhythmias were associated with the presence of left ventricular hypertrophy and aortic regurgitation as observed on echocardiography. These abnormalities were also associated with decreased coronary reserve demonstrated by thallium myocardial scintigraphic testing. Kato and coworkers (74) found that scintigraphic abnormalities in 21 TA patients were associated with increased baseline QT dispersion. In these patients, no significant coronary artery stenosis was detected on angiography (74). Only sporadic case reports describe conduction defects in TA. An interesting report concerns a 56-year-old woman with TA that developed complete AV block and LBBB that improved rapidly after steroid treatment was commenced (75). In another report, a patient who died due to complete AV block had scar formation and diffuse infiltration of lymphocytes in the cardiac conduction system on autopsy, implying that this pathology may have been a consequence of the autoimmune process (76). Kawasaki Disease Kawasaki disease (KD) is an acute febrile infantile disease responsible for acquired heart disease in children. Acute systemic arteritis in KD particularly affects the coronary arteries. Noninvasive and high sensitivity methods are essential for its detection. Suzuki and coworkers (77) detected marked tachycardia by 24-hour ECG monitoring in 26 KD patients during the acute phase of their disease. This finding was associated with the development of coronary arterial lesions (77). Another study in 56 patients with KD showed that QT dispersion, as defined by the difference between maximum and minimum QT inter-

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vals of 60 ms or more, is a reliable predictor for detection of severe involvement of coronary arteries (78). ECG abnormalities are seen frequently during acute and convalescent KD. These abnormalities are most prevalent in the first month of the disease and include T-wave changes and prolonged PR and QT intervals (79). These ECG changes usually do not predict the type of echocardiographic abnormalities (79). Complete AV block has also been described during the acute phase of KD (80). Myocardial ischemia is most common during the first year of the disease but can occur later in young adulthood as well. Nakada (81) reported an 11-year-old patient with suspected myocardial ischemia who had VT and frequent ventricular premature contractions on holter ECG, 9 years following the onset of KD. Two other young adults required implantable defibrillators because of VT caused by presumed KD in infancy (82). Possible myocardial ischemia was considered to be one 1of the causes of the ventricular arrhythmia. In a recent study, Sumitomo and coworkers (83) reported an association between SA node dysfunction, AV node dysfunction, and ventricular arrhythmia in 40 KD patients who had moderate to severe coronary artery disease. Behcet’s Disease (BD) BD is a chronic inflammatory disease characterized by recurrent oral aphthous and genital ulcerations often with ocular and dermal involvement. Vasculitic changes leading to thrombosis and organ damage are dominant pathological features of BD. Cardiac manifestations such as pericarditis, myocarditis, coronary vasculitis, acute myocardial infarction, arrhythmias, and conduction defects are not as rare as previously believed (84). It has been acknowledged that ventricular arrhythmias are more common in Behcet’s patients than in healthy controls, although its pathophysiology remains unclear (85). Several studies have shown that QT dispersion values are significantly higher in Behcet’s patients compared with controls (86,87). The hypothesis is that increased differences in myocardial recovery times in Behcet’s patients, as expressed by QT dispersion value, are due to myocardial involvement resulting particularly from microvascular coronary disturbance, and not as of autonomic dysfunction (86-88). Kinmli and coworkers (88) observed that BD patients had significantly increased QT dispersion, a high incidence of positive late potentials, and more complex ventricular arrhythmias, whereas heart rate variability measures did not suggest a clear autonomic abnormality. Conduction impairment has been reported in BD in conjunction with complex cardiac events such as complete AV block with superior vena cava obstruction; complete AV block with atrial fibrillation; intra-Hisian block with aortic regurgitation; first-degree AV block and RBBB with aortic regurgitation and Valsalva aneurysm rupture; and, complete AV block with concomitant sub-

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aortic obstruction (84,89-92). In 1 case, complete AV block was recorded in a 28-year-old woman with no concomitant cardiac abnormalities (93). Although the etiology of conduction defects in BD is not clear, inflammation of the conduction system may be the primary etiology (89-93). Wegener’s Granulomatosis Wegener’s granulomatosis (WG) is a necrotizing vasculitis that mainly affects the respiratory tract and kidneys. Involvement of the heart had been reported in 6-44% of patients (94). In 15% of these patients the cardiac conduction system is involved. Few case studies demonstrated arrhythmias in WG, particularly supraventricular arrhythmias (94,95). James and Birk (95) were the first to report 3 cases of atrial tachycardia, flutter, and fibrillation. They associated these cases to sinus node dysfunction. Histology analysis in these cases revealed that the sinus node was severely affected by granulomatous changes, associated with sinus node arteritis. Several case studies demonstrating complete AV block associated with WG have been published (96-101). In most cases, the conduction defect resolved after initiating glucocorticoids and cyclophosphamide therapy. Several patients required a permanent pacemaker implantation. Limited WG presenting with complete AV block is very rare and has been published in only few case reports (102,103). Most autopsy studies of these cases reveal an inflammatory process with granulomatous lesions, hyalinization, and necrosis of the conduction system that include the AV node, bundle of His, and right and left bundle branches. As opposed to these cases which usually involved other structures in the heart, Khurana and coworkers (104) described a WG patient with new onset LBBB and right-axis deviation with an otherwise normal structure of the heart. Sarcoidosis Sarcoidosis is a granulomatous disease of an unknown cause characterized by multisystem involvement, in particular, infiltration of the lungs, reticuloendothelial system, and the skin. Cardiac involvement is not often recognized but is demonstrated in 20 to 58% of autopsies and is considered to be the major cause of death (105). Atrial and ventricular arrhythmias are frequently observed, the latter being the leading cause of death in cardiac sarcoidosis (106-110). Although VT is relatively common in advanced cardiac sarcoidosis, it may also be the presenting manifestation of cardiac involvement (106,107). Winters and coworkers (107) studied 7 sarcoid patients with VT and found that all patients had electrocardiographic abnormalities at rest and left ventricular wall motion abnormalities on echocardiography. Sustained VT was easily induced in all of these patients. Despite corti-

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costeroid and anti-arrhythmic drug therapy, 2 patients had SCD, 4 had recurrence of VT, and 4 patients had an automatic defibrillator implanted. In a recent study, Banba and coworkers (111) demonstrated that VT is not closely linked with disease activity as estimated by gallium-67 citrate scintigraphy. VT often develops in advanced stages of the disease and is not necessarily improved following corticosteroid treatment. Although arrhythmias in cardiac sarcoidosis are often refractory to corticosteroids and antiarrhythmic agents, in some patients this therapy may be beneficial. Worth mentioning is the case of a 38-year-old patient with sarcoidosis who presented with polymorphic VT and was treated successfully with corticosteroids, metoprolol, and cibenzoline (109). In another report a young woman with complete AV block due to cardiac sarcoidosis was successfully managed with infliximab as a first-line treatment (112). In necropsy studies, the typical pathophysiology findings are noncaseating granulomas which infiltrate the myocardium and eventually form fibrotic scars (107,108). The left ventricular free wall and the interventricular septum are the most common sites involved in patients with arrhythmias and conduction defects (113). ECG abnormalities are found in 22-51% of sarcoid patients. These changes include T-wave abnormalities, Q-waves, ST-T changes, fascicle blocks, and varying degrees of AV blocks, particularly complete AV block (114118). Yoshida and coworkers (117) studied 89 patients with high-degree AV block who were admitted for a permanent pacemaker insertion; 10 of these patients had sarcoidosis. This study and other case studies emphasize the fact that any AV block, especially in young adults, should raise the possible diagnosis of sarcoidosis (116). The pathophysiology of AV block is not entirely deciphered in sarcoidosis, yet it is frequently explained by involvement of the interventricular septum (119). Administration of glucocorticoids appears to be only partially useful in treating AV block in cardiac sarcoidosis patients (115-117). Banba and coworkers (111) investigated 10 sarcoid patients with complete AV block and found that it develops mainly during the active phase of the disease and early treatment with corticosteroids might improve the conduction disturbance. Anti-Ro and anti-La Antibodies Transplacental penetration of anti-SSA/Ro and antiSSB/La ribonucleoprotein antibodies from the mother, who may have SLE, SSc, or SS, or may even be entirely asymptomatic, into the fetal circulation is associated with congenital conduction disturbances. The most common and studied conduction defect is complete heart block (CHB) (120-123) reaching approximately 2-3% of neonates whose mothers are positive for anti-SSA/Ro and SSB/La. The risk of recurrence of CHB in a subsequent child remains limited to 10-16%.

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The mortality of CHB in utero and in the first months of life is an estimated 16-19%. A pacemaker is required in about 66% of cases in childhood and eventually almost 100% of children will require one by adulthood (120). Curative treatment of CHB is based on dexamethasone or betameth1asone therapy that crosses the placenta in an active form (124). While the precise pathogenetic mechanism of autoantibody-mediated tissue injury is not clear, it has been demonstrated in adult rabbit and human fetal hearts that sera containing anti-SSA/Ro antibodies induce AV blocks and inhibit L-type calcium currents in isolated ventricular myocytes. It is now well recognized that the conduction defect occurring in infants is closely related to the arrhythmogenic effect of these antibodies on the conduction system of the heart (125). In addition to CHB in neonates, first- and seconddegree AV blocks have been reported and may progress to CHB (124). Mazel and coworkers (126) found that passive transfer of human anti-SSA/Ro and SSB/La antibodies into pregnant mice induced bradycardia and first-degree AV block of the progeny, suggesting a SA node involvement. Brucato and coworkers (127) prospectively studied 20 pregnancies in anti-SSA/Ro-positive mothers; 3 neonates had sinus bradycardia with no apparent cause. In all 3 cases, bradycardia disappeared after 10 days with no sequelae. On the other hand, a study published recently had not found any significant difference in mean heart rate of 58 infants born to mothers with anti-SSA antibodies as compared with 85 infants born to mothers with CTD who were negative for both anti-SSA and antiSSB (128). Whether or not QTc prolongation is more common in children born to anti-Ro/SSA-positive mothers is not clear as there are conflicting reports in the literature. Gordon and coworkers (129) found QTc prolongation in babies from anti-Ro-positive mothers, in particular, those with siblings with congenital heart block. Cimaz and coworkers (130) noted a prolongation of the mean QTc interval in 21 children born to anti-SSA/Ro-positive mothers compared with 7 infants born to anti-SSA/Ronegative mothers with CTD. QTc prolongation, in these cases, was transient and resolved during the first year of life (131). VT secondary to prolongation of the QT interval in a fetus with immunomediated CHB also has been described (132). Motta and coworkers (133) found that mean corrected QT value of infants born to anti-SSA/Ro-positive mothers was slightly prolonged compared with the control group (children born from mothers with anti-extractable nuclear antigen-negative CTD), but such a difference only approached statistical significance (P ⫽ 0.060). Gerosa and coworkers (134) reported no difference in QTc prolongation prevalence between children born to mothers with positive anti-Ro as compared with mothers with negative anti-Ro/SSA. However, the authors found that children born to mothers with autoimmune diseases, independently of being anti-Ro/SSA-positive or -nega-

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tive, had a significantly higher prevalence in QTc interval prolongation than children born to healthy mothers. Another study, comparing ECGs of 58 consecutive children aged 0 to 2 months born to anti-SSA/Ro-positive mothers to a control group of 85 infants aged 0 to 2 months born to anti-SSA/Ro-negative mothers with CTD, revealed no difference of QTc, PR, and heart rates (128). This finding remained true at 2 and 4 months of life as well. Until recently it was supposed that CHB is due to vulnerability of the fetal heart, and anti-SSA/Ro antibodies were not considered pathogenic for the adult heart (135). Gordon and coworkers (135) did not find any statistically significant abnormalities of PR, QRS, or QTc in ECGs of adults with anti-SSA/Ro antibodies. Furthermore, Costedoat-Chalumeau and coworkers (136) reported no difference in mean QTc duration evaluating 32 anti-Ro/SSA-positive in comparison with 57 anti-Ro/ SSA-negative CTD patients. In contrast, Lazzerini and coworkers (43) did manage to detect a significant prolongation of the mean QTc interval in 31 adult patients with anti-SSA/Ro-positive CTD (⬎440 msec, about 50% of patients) in comparison with 26 anti-SSA/Ro-negative CTD patients. Another recent study performed in a large cohort of SLE patients (n ⫽ 150, 38% anti-Ro/SSA-positive) confirmed the results of Lazzerini and his colleagues demonstrating a 12.6 odds ratio having a prolonged QTc in anti-Ro/SSA-positive SLE patients (137). More recently, a 24-hour ECG monitoring study confirmed that anti-Ro/SSA-positive CTD patients commonly showed QTc prolongation, persisting equally over all of the recording time. Moreover, positive patients exhibited a fivefold increase of complex ventricular arrhythmias rates with a direct correlation between the global-mean-24-hour-QTc and the ventricular arrhythmic load (138). A very recent and interesting study of Nakamura and coworkers (139) elaborated on the selective inhibitory effect on the KCNH2 (HERG) potassium channel by serum or IgG from an anti-Ro/SSA-positive young female with extreme QTc prolongation, episodes of Torsades de pointes, and recurrent syncope. Since such a channel plays a pivotal role in the cardiac repolarization by conducting the Ikr currents, the authors concluded that a cross-reaction of anti-Ro/SSA antibodies with the KCNH2 channel may be involved in the pathogenesis of the arrhythmic disturbances observed in the patient and possibly in other anti-Ro/SSA-positive subjects with ECG abnormalities. Antiphospholipid Syndrome Accelerated atherosclerosis and valvular heart disease are the main cardiac manifestations of the antiphospholipid syndrome (APS). Conduction defects in APS are rare but have been reported in several case studies. Kupferminc and coworkers (140) reported a postpartum woman positive for anticardiolipin antibodies and the lupus anticoagulant who de-

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veloped a severe conduction defect following an episode of preeclampsia. She was successfully treated with steroids and plasmapheresis. APS was found to be the cause of fetal bradycardia in 2 pregnant women during their second trimester (141). Very few cases of congenital CHB of the newborn in mothers with APS have had described (142144). James and coworkers (145) described a young woman with SCD due to CHB whose mother had serological but no clinical evidence of APS. A fatal arrhythmia was reported to be the direct cause of death in 2 patients with the catastrophic APS (146). DISCUSSION Arrhythmias and conduction defects are important manifestations of cardiac involvement in patients with rheumatic diseases. These cardiac rhythm disturbances may be mild but also may lead to a fatal outcome. The underlying arrythmogenic mechanisms in CTD are probably diverse, but myocardial damage and fibrosis seem to be the most important factors. Atherosclerosis plays an important role contributing to the pathogenesis of conduction defects and arrhythmias in autoimmune diseases (147). In autoimmune conditions, higher rates of cardiovascular morbidity and mortality are often detected, primarily due to accelerated atherosclerosis. Cardiovascular diseases and in particular ischemic heart disease represent the main cause of death in RA patients. Given the fact that most SLE patients are young women, coronary artery disease reaches significantly high prevalence rates ranging from 6 to 10%, and the risk of developing clinical symptoms is up to 4 to 8 times higher compared with matched healthy controls. Atherosclerosis is also enhanced in SS, SSc, APS, and several vasculitides. This accelerated immune-mediated process of atherosclerosis provides a good platform for the development of conduction abnormalities and arrhythmias. While several rheumatologic diseases are associated with conduction abnormalities and arrhythmias, these abnormalities also may be an adverse effect of the medications commonly used by such patients. Corticosteroids, and in particular, high-dose intravenous methylprednisolone, are associated with tachyarrhythmias such as AF, atrial flutter, SVT, VF, and less commonly bradycardia (148). Methotrexate may induce RBBB and ventricular arrhythmias (149) as well as AF when given in combination with the anti-tumor necrosis factor inhibitor etanercept (150). Chloroquine is associated with a high incidence of cardiac conduction disorders, including bundle-branch blocks and incomplete or complete AV blocks. Hydroxychloroquine was safer than chloroquine in terms of heart conduction disorders (151). No randomized controlled trials have been conducted to assess the proper management of rheumatologic patients with cardiac conduction disturbances and arrhythmias. However, it is important to identify patients at risk

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that should be routinely examined by simple techniques such as ECG, echocardiogram, and continuous telemetry recordings. Regarding arrhythmias, therapy is similar to that used for patients without underlying autoimmune conditions. Cardiac manifestations are best managed in consultation with a cardiologist. Commencing corticosteroids should always be considered particularly at early stages of the disease. REFERENCES 1. Wisowska M, Sypua S, Kowalik I. Echocardiographic findings and 24-h electrocardiographic Holter monitoring in patients with nodular and non-nodular rheumatoid arthritis. Rheumatol Int 1999;18:163-9. 2. Tlustochowicz W, Piotrowicz R, Cwetsch A, Raczka A, Kramarz E, Nowak J. 24-h ECG monitoring in patients with rheumatoid arthritis. Eur Heart J 1995;16:848-51. 3. Goldeli O, Dursun E, Komsuoglu B. Dispersion of ventricular repolarization: a new marker of ventricular arrhythmias in patients with rheumatoid arthritis. J Rheumatol 2008;25:447-50. 4. Cindas A, Gökçe-Kutsal Y, Tokgözoglu L, Karanfil A. QT dispersion and cardiac involvement in patients with rheumatoid arthritis. Scand J Rheumatol 2002;31:22-6. 5. Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJF. Rheumatoid arthritis and macrovascular disease. Rheumatology 2003;42: 292-7. 6. Parnes E, Krasnoselskii M, Tsurko VV, Striuk RI. Long-term prognosis in patients with rheumatoid arthritis depending on baseline variability of cardiac rhythm. Ter Arkh 2005;77:77-80. 7. Evrengul H, Dursunoglu D, Cobankara V, Polat B, Seleci D, Kabukcu S, et al. Heart rate variability in patients with rheumatoid arthritis. Rheumatol Int 2004;24:198-202. 8. Anichkov DA, Shostak NA, Ivanov DS. Heart rate variability is related to disease activity and smoking in rheumatoid arthritis patients. Int J Clin Pract 2007;61:777-83. 9. 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;24:683-9. 10. Kitas GD, Banks M, Bacon PA. Cardiac involvement in rheumatoid disease. Clin Med 2001;1:18-21. 11. Villecco AS, de Liberali E, Bianchi FB, Pisi E. Antibodies to cardiac conducting tissue and abnormalities of cardiac conduction in rheumatoid arthritis. Clin Exp Immunol 1983;53: 536-40. 12. Ahern M, Lever JV, Cosh J. Complete heart block in rheumatoid arthritis. Ann Rheum Dis 1983;42:389-97. 13. Arakawa K, Yamazawa M, Morita Y, Kobayashi I, Horiguchi Y, Kamimura D, et al. Giant rheumatoid nodule causing simultaneous complete atrioventricular block and severe mitral regurgitation: a case report. J Cardiol 2005;46:77-83. 14. Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 2005;52:402-11. 15. Mandell BF. Cardiovascular involvement in systemic lupus erythematosus. Semin Arthritis Rheum 1987;17:126-41. 16. Hejtmancik MR, Wright JC, Quint R, Jennings FL. The cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 1964;68:119-30. 17. Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine 1971;50:85-95. 18. Maier WP, Ramirez HE, Miller SB. Complete heart block as the initial manifestation of systemic lupus erythematosus. Arch Intern Med 1987;147:170-1.

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