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Iatreia

Print version ISSN 0121-0793

Iatreia vol.26 no.4 Medellín Oct./Dec. 2013

 

ARTÍCULO DE REVISIÓN

 

Heart disease characteristics in patients with systemic lupus erythematosus

 

Características de la afección cardíaca de los pacientes con lupus eritematoso sistémico

 

 

Santiago Patiño Giraldo1; Luis Alonso González Naranjo2; Gloria María Vásquez Duque3; Mauricio Restrepo Escobar4

 

1 MD and Surgeon, Resident of Internal Medicine, Faculty of Medicine, University of Antioquia, Medellín, Colombia.

2 Internist and Rheumatologist, Assistant Professor, Rheumatology Section, Department of Internal Medicine, Faculty of Medicine, University of Antioquia, Medellín, Colombia. drsapg@gmail.com

3 Internist and Rheumatologist, Doctor of Immunology, Associate Professor, Rheumatology Section, Department of Internal Medicine, Faculty of Medicine, University of Antioquia, Medellín, Colombia.

4 Internist and Rheumatologist, Lecturer, Rheumatology Section, Department of Internal Medicine, Faculty of Medicine, University of Antioquia, Medellín, Colombia.

 

 

Received: July 23, 2012
Accepted: February 19, 2013

 

 


SUMMARY

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by periods of activity and remission in which any organ can be affected. Cardiovascular involvement represents an important cause of mortality in SLE patients after infections. Indeed, valvular involvement in a patient with cutaneous lupus is considered the first sign of a systemic condition. These patients may have an isolated condition in the pericardium, myocardium, endocardium, valves and vascular bed or an overall involvement. Cardiac alterations may be present in more than 50% of patients at any stage of disease progression, especially in men, who have a higher risk of cardiovascular disorders. This paper is a review of the characteristics of cardiac involvement in SLE patients and its clinical manifestations, diagnosis and treatment.

KEY WORDS

Atherosclerosis, Cardiovascular diseases, Systemic Lupus Erythematosus, Morbidity, Mortality.


RESUMEN

El lupus eritematoso sistémico (LES) es una enfermedad de etiología autoinmune caracterizada por episodios de crisis y remisiones, en la que se puede afectar cualquier órgano. Luego de las infecciones, las afecciones del sistema cardiovascular explican una parte importante de la mortalidad en pacientes con LES. De hecho, el compromiso valvular en un paciente con lupus cutáneo fue el primer indicio para considerar que esta era una enfermedad sistémica. En dichos pacientes se puede afectar aisladamente cualquier estructura cardiovascular: pericardio, miocardio, endocardio, válvulas y lechos vasculares, y también puede ocurrir compromiso global. Las alteraciones cardíacas se pueden encontrar en cualquier etapa de la evolución de la enfermedad y suelen estar presentes en la mitad o más de los pacientes especialmente en hombres, que tienen más riesgo de compromiso cardiovascular. El presente artículo es una revisión de las características de la afección cardíaca en los pacientes con LES; se incluyen sus manifestaciones clínicas, el diagnóstico y el tratamiento.

PALABRAS CLAVE

Aterosclerosis, Enfermedades Cardiovasculares, Lupus Eritematoso Sistémico, Morbilidad, Mortalidad.


 

 

INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by periods of activity and remission. Cardiac conditions are common in SLE and were one of the first symptoms described in the literature. All cardiac structures, the pericardium, myocardium, endocardium, valves and vascular beds, may be affected individually or as part of an overall condition (1,2) that varies in its frequency and severity (3). The correct diagnosis and treatment are based on the clinician's understanding of the frequency, etiology and clinical presentation of cardiac involvement in SLE patients. In this article, the characteristics, clinical manifestations, diagnosis and treatment of these conditions are reviewed.

 

PERICARDIUM INVOLVEMENT

Pericarditis is one of the most common findings in SLE patients, and it is included among the American Rheumatism Association/American College of Rheumatology (ARA/ACR) classificatory criteria. This condition is reported in 25% to 50% of patients, depending on the series (4,5), and is mostly asymptomatic. Cardiac tamponade may be the initial manifestation of the disease; it is present in 1% to 4% of cases (6-8). Pericarditis may be acute or chronic (9) or may have other presentations, such as hemopericardium (10,11).

Immunofluorescence studies show immunoglobulin and C3 complement deposits, which suggest that pericarditis is mediated by immune complexes, although this hypothesis is not completely clarified (12). Moreover, pericardial effusion is produced by a decrease in the lymphatic and venous flow of the myocardium secondary to increased pressure in the right atrium and hypoalbuminemia.

Pericarditis occurs most frequently in women. Together with other organ involvement, it may present dull precordial pain (39%), dyspnea (61%) and pericardial friction rub (6%) (2,13). Typical electrocardiographic changes (39%), cardiomegaly on chest radiographs (44%) and pericardial effusion on echocardiogram (94%) are often seen in paraclinical studies (14). Patients with pericarditis have lower levels of albumin, serum proteins and C4, as well as proteinuria, high C-reactive protein (CRP) and a positive score for SLE disease activity (4,15).

Mild involvement can be treated with NSAIDs or low doses of steroids, and severe involvement can be treated with intravenous methylprednisolone. Other immunosuppressants have been used in recurrent cases (13). Cardiac tamponade cases and those that do not respond to drug therapy may require surgery (16).

 

MYOCARDIAL DISEASES

Based on autopsy studies, 40% to 60% of SLE patients have myocardial involvement, but only 5% to 10% show clinical manifestations. In a retrospective study, Law et al. (17) identified, over an eight-year period, 11 cases of myocarditis as systolic function involvement on an echocardiograph with no evidence of coronary disease. This result sustains the rareness of clinical lupus myocarditis. All of the patients were females, and for eight of them, myocardial involvement was the initial manifestation of lupus (73%).

Histopathological examination of SLE cardiomyopathy shows mononuclear perivascular and interstitial invasion with myocardial degeneration and fibrosis (18,19) as well as immune complexes and complement deposits on the vascular walls and in the perivascular spaces (12). For unknown reasons, these findings appear on the posterolateral segments and are similar to those of viral myocarditis (20). Findings similar to giant cell myocarditis have been reported in the literature (21).

The clinical features of dyspnea (76%), edema, orthopnea and crepitus (72%), tachycardia and jugular venous distension (54%) or cardiogenic shock are indistinguishable from other types of myocarditis (22). In more than half of the patients, other systems are involved, particularly the skin, kidneys, central nervous system and gastrointestinal tract (17). Laboratory findings show lymphopenia, complement consumption, positive anti-DNAs, lupus anticoagulant (LA) and elevated creatine kinase. Additionally, some reports associate lupus myocarditis with elevated anti Ro/SSA (23). Diffuse contractility involvement with or without a decrease in ejection fraction in echocardiography (24), disorders on the myocardial perfusion scintigraphy (25,26) and, recently, abnormalities on magnetic resonance imaging (27-29) sustain the diagnosis.

Regardless of the severity of the condition, prompt treatment with high doses of steroids is required. Cyclophosphamide (22,30,31) and intravenous immunoglobulin (IVIG) (32) have also been used to treat lupus myocarditis.

Because myocardial involvement can be linked to atherosclerosis, high blood pressure, nephropathy, heart valve disease or toxic reaction to drugs, its association with lupus is hard to define and must be considered a diagnosis by exclusion (13).

 

VALVE INVOLVEMENT

Valve involvement is common in SLE patients, particularly in those with positive lupus anticoagulant. The prevalence of this condition is variable and will depend on the study: 13% to 65% on autopsies, 9% to 28% on transthoracic echocardiograms (TTE) (33,34) and 53% to 73% on transesophageal echocardiogram (TEE) (35).

Although its physiopathology is not clear, it is thought to have an immunological basis because of the association with lupus anticoagulant, immune complexes deposits in the valves, especially in interaction with anticardiolipins and anti-β2-glycoprotein-I, and the positive response to steroids (1). The most common finding is the thickening of the left heart valves, followed by Libman-Sacks endocarditis and other nonspecific lesions. Valve regurgitation prevails, while stenosis is rare (36).

A study that analyzed the echocardiograms and myocardial perfusion of 60 asymptomatic patients identified an association between valve involvement and disease progression (more than eight years), elevated CRP levels and reduced C3 and C4 levels. An association was found between perfusion defects and an increase in the right ventricle pressure, with higher levels of anticardiolipin IgG and anti-β2-glycoprotein-I (37). Furthermore, Jensen-Urstad et al. identified an association between valve involvement and elevated VLDL, triglycerides and homocysteine (38).

Patients with valve involvement may have serious complications, such as cerebrovascular events, peripheral embolism, infectious endocarditis and heart failure (35); however, there is no specific therapy for these patients other than the standard treatment for SLE.

Libman-Sacks endocarditis

In 1924, Libman and Sacks described postmortem findings of verrucous valvular lesions, especially involving the mitral valve. Histopathological studies have identified two types of lesions: active lesions, characterized by fibrin accumulations, focal necrosis and mononuclear infiltrates, and scarring lesions with vascularized fibrous tissue and calcifications (13).

The vegetations are located on the base of the valve, making most cases asymptomatic and occasionally resulting in heart murmurs. In 3% to 4% of cases, hemodynamic compromise is present; however, only half of these cases require surgical treatment. Some patients may develop infectious endocarditis (7%), cerebrovascular disease and peripheral embolism (13%). The prevalence of these complications has decreased since the introduction of corticosteroid treatment: these drugs are the treatment of choice (prednisolone 1 mg/kg/day) for symptomatic patients, when necessary.

 

CONDUCTION SYSTEM DISEASE

These disturbances present with other cardiovascular conditions in 16% of patients and as a single condition in 3.2% of patients (39). Sinus tachycardia is the most common heart rhythm alteration in SLE patients. It can be secondary to fever, anemia, pulmonary embolism and other cardiac abnormalities (13). Nearly 25% of the patients have a shortened PR interval (4). Although rare, second-degree atrioventricular block and complete non-congenital heart block have been described (40,41) and are associated with positive levels of RNPU1 antinuclear antibodies (42), antiRo antibodies and disease activity (41). Among the physiopathological mechanisms proposed, vasculitic disorders, mainly affecting the conduction system, and vacuolar myopathy are described (43). Most patients are asymptomatic; however, atrioventricular blocks with presyncope or syncope have been described.

Because this is an infrequently occurring condition, there is no specific treatment described in the literature for SLE patients other than that described for non-lupus patients who have electrocardiographic findings. However, some cases with AV blocks respond to steroids without the need for a permanent pacemaker (43-45).

 

HEART FAILURE

Systolic or diastolic left ventricular function involvement is noted in 5% to 31% of SLE patients, secondary to coronary disease (46). On the target organ assessment of the LUMINA cohort study, 42% of patients had isolated heart failure, 4.6% had heart failure associated with acute myocardial infarction (AMI) and 14% had heart failure associated with coronary disease (39). Heart failure hospitalization risk is 3.01, 1.39 and 1.33 times more frequent in SLE patients aged 34 to 44 years, 45 to 65 years and older than 65 years, respectively (47).

In a prospective study of 54 patients, diastolic alteration was associated with disease activity (44% versus 3.4%) rated higher than 5 on the SLEDAI index (Systemic Lupus Erythematosus Disease Activity Index) (48).Other studies add age and the time course of the disease to this relationship (46). Clinical and paraclinical findings do not differ from those of heart failure with other etiologies.

The treatment of choice for these patients, when needed, is angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers and diuretics.

 

CORONARY DISEASE AND ACUTE MYOCARDIAL INFARCTION

In 1976, Urowitz's group described a bimodal mortality for SLE patients: an early mortality associated generally with the disease activity, and a late mortality associated with AMI (20% to 45%, depending on the study) (49-52). In recent years, this phenomenon, taken as an inflammatory condition, makes lupus an in vivo model of the atherosclerotic process, although an accelerated atherosclerosis in SLE patients is well known.

Clinical cases of atherosclerosis (angina or AMI) account for 6% to 12% of patients or nearly 40% when subclinical cases are included (49,50), although some authors report a prevalence of 95% (39). LUMINA, a very large and multiethnic cohort, established a 6.8% rate of cardiovascular damage in 6.6 years (39).

Lupus increases the risk of having an AMI by 50 times in the 34-to 44-year age range. Lupus carries 8.5 times the risk of hospitalization and 5 times the risk of a cardiovascular event, all at an earlier age than in the general population (51-53).

Although the prevalence of traditional risk factors is high in patients with lupus, it can not explain their elevated frequency in SLE patients (54-56). Three mechanisms for the coronary circulation involvement in SLE patients have been suggested, as follows: arteritis (the rarest), tendency toward thrombosis (57) and accelerated atherosclerosis (58,59).

Traditional risk factors

The International Registry for Atherosclerosis (SLICCRAS) conducted a multicenter study of SLE patients. At the moment of diagnosis, their average age was 34 years, 33% showed high blood pressure, 36% had dyslipidemia, 16% were smokers and 3.6% had diabetes (60). After three years of follow-up, these percentages had almost duplicated, as 58% had high blood pressure, 60% had dyslipidemia, 43% were smokers and 5% had diabetes mellitus (61). In the Lupus Hopkins cohort study, the percentages were similar: 46% had high blood pressure, 55% had dyslipidemia, 37% were smokers, 6% had diabetes and 70% had a sedentary lifestyle.

The persistence of hypercholesterolemia at the beginning of the disease seems to have an influence on accelerated atherosclerosis (62). Lipid disorders are identified at an early age and have a high prevalence, even in cases of pediatric and juvenile lupus (50% to 85%, depending on the study) (63). Elevated triglycerides and lipoprotein(a) with reduced cHDL and normal or slightly elevated LDL is described as the lupus dyslipidemia pattern (64). Hayata et al., studying a group of 40 patients with an average age of 20 years, identified that 85% of them had high-risk alterations of lipid disorders, especially reduced cHDL (65).

Metabolic syndrome (MS) is present in 20% to 38% of lupus patients (66-69). MS is more prevalent in SLE patients under 40 years of age (15.8% versus 4.2%) compared with a control population of similar age, while this difference is not seen in older patients. This result suggests that MS inflammatory mechanisms play a predominant role in younger patients and a multifactorial etiology in older patients. These patients have three and eight times higher risks of cardiovascular disease than lupus patients without MS and MS patients without lupus, respectively (68). A late diagnosis, nephrotic-range proteinuria and a high injury rate have been linked to MS (66).

Non-traditional risk factors

Other factors have been related to a higher prevalence of cardiovascular events, such as lipoprotein(a) (70), oxidized LDL and its antibodies, antibodies for HDL and fractional Apo A1 (71), antiphospholipid antibodies, serum amyloid A, low activity of lipoprotein lipase (63), acute phase reactants (CRP, fibrinogen) and hyperhomocysteinemia (49,72).

Serum amyloid A is a protein coexpressed with phospholipase A2 as a factor of accelerated atherosclerosis in SLE patients. When bonded to cHDL, this protein triggers the lipolytic activity of phospholipase A2 that promotes endothelial damage (62).

Lupus anticoagulant is a risk factor for arterial thrombosis, including coronary arteries (73). Among this antibody family, β2-glycoprotein is of great interest because it appears to have atheroprotective effects (74).

Finally, in a 5-year prospective study of 94 lupus patients, early menopause and a slightly higher risk of coronary calcifications seemed to contribute to a higher risk of cardiovascular disease in SLE patients (OR: 1.19; 95% CI: 1.01-1.35) (75).

 

CARDIOVASCULAR RISK ASSESSMENT IN LUPUS

Despite the large number of indexes used to stratify the risk of the general population, none has achieved a way to correlate a higher incidence of cardiovascular events with lupus. Chung et al. compared two index scores for cardiovascular risk (Framingham and PDAY) and the calcium levels of 93 patients with lupus and 63 controls (70). SLE patients had a higher prevalence of coronary calcifications (19.4% versus 6.2%) and a higher calcium score (30 ± 200 versus 4 ± 30 units) but no differences in the risk index scores. Furthermore, 99% of patients had a low risk according to the Framingham index, despite the presence of important coronary calcifications. Other risk scores have been evaluated, such as the Framingham index adjusted to coronary age, the Reynolds Risk Score and the Reynolds Risk Score adjusted to calcium scores, without an adequate stratification of cardiovascular risk (76).

The best method for diagnosing coronary disease in SLE patients is unknown. The correlation between non-invasive studies, echocardiography (77) or gammagraphy and coronarography is low (78).

Korkmaz et al. (79) analyzed the cases of AMI reported in the literature for SLE patients under 35 years of age and found 50 cases (41 women and 9 men), with an average age of 20 years. Based on the coronarographic findings, the patients were divided into three groups, as follows: 1. Normal coronary or thrombosis patients (32%), characterized by an early appearance of the disease, positive lupus anticoagulants and higher activity scores; 2. Coronary aneurysm or arteritis patients (24%), characterized by a moderate time of evolution of the underlying disease, active disease and high renal involvement; and 3. Coronary atherosclerosis patients (44%), with longer-standing SLE, a higher frequency of cardiovascular risk factors and an absence of lupus activity.

Therapy depends on the origin of the problem, which can be inflammatory, immune activity-mediated or related to complications of the disease and its treatment or the treatment for another associated process. In general, this treatment is not different from that of the general population (beta-blockers, ACE-I/AIIRA, statins and aspirin). The exception is for vasculitis, which requires 1-1.5 mg/kg/day prednisolone, and the use of anticoagulants and vasodilators for antiphospholipid syndrome (13).

Statins treatment has known effects on lipids and has been shown to reduce levels of anti-DNA and lupus nephritis, for which its use with all SLE patients has been suggested. However, a recent controlled clinical trial dismisses the clinical utility of this treatment (80). In contrast, a cohort study found a 70% reduction in cardiovascular mortality and an 11-month gain of a healthy life in patients who underwent aspirin treatment. Despite all these data, no clinical study has validated these observations (46).

 

TREATMENT COMPLICATIONS

Glucocorticoids

Steroids are the backbone of SLE treatment, although they have been linked to cardiovascular risk factors such as dyslipidemia, high blood pressure, carbohydrate intolerance and accelerated atherosclerosis. Moreover, these drugs may increase the adipose tissue in subepicardial areas, especially those around the epicardial arteries, and may also increase the thickness of the right ventricle walls (81). When adjusted for several variables, the Hopkins cohort analysis (49) associated a 10-mg increase in the prednisolone dose with a positive variability of 7.5 ± 1.46 mg/dL total cholesterol, 1.1 mm Hg in mean blood pressure and 5.5 ± 1.23 lb of body weight. In the study, accelerated atherosclerosis was related to the dosage (RR: 1.5; 95% CI: 1.2-2.4) but not to high doses (RR: 1; 95% CI 0.3-3) or methylprednisolone pulses (RR: 1.1; 95% CI 0.7-1.8). Glucocorticoid effects are dual. Low doses protect the endothelium with anti-inflammatory action, but high doses disrupt the cardiovascular metabolism. The line between these two effects varies from one patient to the other. Finally, in the Puerto Rico Cohort (67), 10 mg of prednisolone or of a similar drug increased the risk of metabolic syndrome in SLE patients (OR: 3.69; 95% CI: 1.22-11.11).

Antimalarial drugs

Antimalarial drugs have immunomodulating properties and play an important role in mild and moderate manifestations of lupus. Additionally, antimalarial drugs counteract hypercholesterolemia associated with steroids (a total cholesterol reduction of 8.9 ± 3.44 mg/dL) (49,62). In the Hopkins cohort, hydroxychloroquine showed a protective effect against thrombosis via several mechanisms of lupus activity control, an antiplatelet effect and a reduction in antiphospholipid antibody scores. A negative correlation between antimalarial drugs and high-sensitivity CRP levels has been described. This correlation is a known cardiovascular risk indicator (82). In comparison, Bellomio (69) and Sabio (83) found a reduction in the risk of metabolic syndrome after the use of antimalarial drugs.

Complete non-congenital AV block is an adverse effect of high doses of antimalarial drugs (chloroquine and hydroxychloroquine) or prolonged treatment (40).

Other immunosuppressants

Azathioprine, cyclophosphamide and tacrolimus have adverse effects on lipid metabolism. Azathioprine has hepatic toxicity and may induce a fatty liver and elevate VLDL. The LUMINA cohort study associated this drug with a hazard ratio (HR) of 1.45 for arterial diseases (84). Similar results were presented by Doria et al. (85), but with no statistical significance. This association is currently being discussed and has led to confusion because patients undergoing azathioprine treatment have higher lupus activity.

Finally, cytotoxic drugs, especially cyclophosphamide, increase LDL cholesterol and predispose patients to accelerated atherosclerosis. However, this is considered a residual effect (86). Cyclophosphamide has a dose-independent cardiotoxic effect.

 

CONCLUSIONS

Systemic lupus erythematosus is an inflammatory autoimmune disease that frequently affects the heart. This involvement is mediated by immune deposits, persistent inflammation and autoantibodies. Pericarditis, myocarditis, heart valve disease, cardiac conduction system failure and, especially, accelerated atherosclerosis must be considered in SLE patients to identify disorders, order appropriate laboratory studies and initiate a specific treatment.

 

REFERENCES

1. Bijl M, Brouwer J, Kallenberg GG. Cardiac abnormalities in SLE: pancarditis. Lupus. 2000;9(4):236–40.         [ Links ]

2. Weich HS v H, Burgess LJ, Reuter H, Brice EA, Doubell AF. Large pericardial effusions due to systemic lupus erythematosus: a report of eight cases. Lupus. 2005 Jun;14(6):450–7.         [ Links ]

3. Pinto L, Velásquez C, Márquez J. Subgrupos de Lupus Eritematoso Sistémico: influencia de la edad de inicio, la raza, el sexo y el perfil de anticuerpos en las manifestaciones clínicas de la enfermedad. Rev Col Reumatol. 2008;15(4):291–8.         [ Links ]

4. Sugiura T, Kumon Y, Kataoka H, Matsumura Y, Takeuchi H, Doi YL. Asymptomatic pericardial effusion in patients with systemic lupus erythematosus. Lupus. 2009 Feb;18(2):128–32.         [ Links ]

5. Cervera R, Font J, Paré C, Azqueta M, Pérez-Villa F, López-Soto A, et al. Cardiac disease in systemic lupus erythematosus: prospective study of 70 patients. Ann Rheum Dis. 1992 Feb;51(2):156–9.         [ Links ]

6. Reiner JS, Furie RA. Cardiac tamponade as an initial manifestation of systemic lupus erythematosus. J Rheumatol. 1989 Aug;16(8):1127–9.         [ Links ]

7. Inase N, Enomoto N, Sakaino H, Shiigai T. Systemic lupus erythematosus presenting with pericardial tamponade and lupus pneumonitis. Jpn J Med. 1989;28(3):362–5.         [ Links ]

8. Zashin SJ, Lipsky PE. Pericardial tamponade complicating systemic lupus erythematosus. J Rheumatol. 1989 Mar;16(3):374–7.         [ Links ]

9. Zashin SJ, Lipsky PE. Pericardial tamponade complicating systemic lupus erythematosus. J Rheumatol. 1989 Mar;16(3):374–7.         [ Links ]

10. Barrera-Ramírez CF, Pineda-Pompa LR, Melo M, Valdez Castro R, Medina-Gómez H, Godina-Alonso G, et al. [Hemorrhagic pericarditis and cardiac tamponade in systemic lupus erythematosus. A case report]. Arch Cardiol Mex. 2005;75 Suppl 3:S3–96–9.         [ Links ]

11. Spodick DH. Hemopericardium in a patient with systemic lupus erythematosus. Circulation. 1999 Feb 9;99(5):723–4.         [ Links ]

12. Bidani AK, Roberts JL, Schwartz MM, Lewis EJ. Immunopathology of cardiac lesions in fatal systemic lupus erythematosus. Am J Med. 1980 Dec;69(6):849–58.         [ Links ]

13. Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, Turriel M, Petri M. Cardiac involvement in systemic lupus erythematosus. Lupus;2005 14(9):683–6.         [ Links ]

14. Man BL, Mok CC. Serositis related to systemic lupus erythematosus: prevalence and outcome. Lupus. 2005;14(10):822–6.         [ Links ]

15. Rosenbaum E, Krebs E, Cohen M, Tiliakos A, Derk CT. The spectrum of clinical manifestations, outcome and treatment of pericardial tamponade in patients with systemic lupus erythematosus: a retrospective study and literature review. Lupus. 2009 Jun;18(7):608–12.         [ Links ]

16. Kamata Y, Iwamoto M, Aoki Y, Kishaba Y, Nagashima T, Nara H, et al. Massive intractable pericardial effusion in a patient with systemic lupus erythematosus treated successfully with pericardial fenestration alone. Lupus. 2008 Nov;17(11):1033–5.         [ Links ]

17. Law WG, Thong BY, Lian TY, Kong KO, Chng HH. Acute lupus myocarditis: clinical features and outcome of an oriental case series. Lupus. 2005;14(10):827–31.         [ Links ]

18. Salomone E, Tamburino C, Bruno G, Di Paola R, Silvestri F. The role of endomyocardial biopsy in the diagnosis of cardiac involvement in systemic lupus erythematosus. Heart Vessels. 1989 Jan;5(1):52–3.         [ Links ]

19. Tamburino C, Fiore CE, Foti R, Salomone E, Di Paola R, Grimaldi DR. Endomyocardial biopsy in diagnosis and management of cardiovascular manifestations of systemic lupus erythematosus (SLE). Clin Rheumatol. 1989 Mar;8(1):108–12.         [ Links ]

20. Abdel-Aty H, Siegle N, Natusch A, Gromnica-Ihle E, Wassmuth R, Dietz R, et al. Myocardial tissue characterization in systemic lupus erythematosus: value of a comprehensive cardiovascular magnetic resonance approach. Lupus. 2008 Jun;17(6):561–7.         [ Links ]

21. Chung L, Berry GJ, Chakravarty EF. Giant cell myocarditis: a rare cardiovascular manifestation in a patient with systemic lupus erythematosus. Lupus. 2005;14(2):166–9.         [ Links ]

22. Disla E, Rhim HR, Reddy A, Ramaprasad S, Taranta A. Reversible cardiogenic shock in a patient with lupus myocarditis. J Rheumatol. 1993 Dec;20(12):2174.         [ Links ]

23. 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 Aug;49(8):627–9.         [ Links ]

24. Ueda T, Mizushige K, Aoyama T, Tokuda M, Kiyomoto H, Matsuo H. Echocardiographic observation of acute myocarditis with systemic lupus erythematosus. Jpn Circ J. 2000 Feb;64(2):144–6.         [ Links ]

25. Laganà B, Schillaci O, Tubani L, Gentile R, Danieli R, Coviello R, et al. Lupus carditis: evaluation with technetium-99m MIBI myocardial SPECT and heart rate variability. Angiology. 1999 Feb;50(2):143–8.         [ Links ]

26. Astorri E, Pattoneri P, Calbiani B, Ridolo E, Dall'Aglio PP. Thallium-201 myocardial perfusion imaging in patients with systemic lupus erythematosus. Minerva Cardioangiol. 2004 Feb;52(1):49–54.         [ Links ]

27. O'Neill SG, Woldman S, Bailliard F, Norman W, McEwan J, Isenberg DA, et al. Cardiac magnetic resonance imaging in patients with systemic lupus erythematosus. Ann Rheum Dis. 2009 Sep;68(9):1478–81.         [ Links ]

28. Kobayashi H, Giles JT, Arinuma Y, Yokoe I, Hirano M, Kobayashi Y. Cardiac magnetic resonance imaging abnormalities in patients with systemic lupus erythematosus: a preliminary report. Mod Rheumatol. 2010 Jun;20(3):319–23.         [ Links ]

29. Saremi F, Ashikyan O, Saggar R, Vu J, Nunez ME. Utility of cardiac MRI for diagnosis and posttreatment follow-up of lupus myocarditis. Int J Cardiovasc Imaging. 2007 Jun;23(3):347–52.         [ Links ]

30. Azzam ZS, Maza I, Zeidan-Shwiri T, Lorber M. Cyclophosphamide restores heart function in a patient with lupus myocarditis. Isr Med Assoc J. 2005 Apr;7(4):266–7.         [ Links ]

31. Chan YK, Li EK, Tam LS, Chow LTC, Ng HK. Intravenous cyclophosphamide improves cardiac dysfunction in lupus myocarditis. Scand J Rheumatol. 2003 Jan;32(5):306–8.         [ Links ]

32. Suri V, Varma S, Joshi K, Malhotra P, Kumari S, Jain S. Lupus myocarditis: marked improvement in cardiac function after intravenous immunoglobulin therapy. Rheumatol Int. 2010 Sep;30(11):1503–5.         [ Links ]

33. Sturfelt G, Eskilsson J, Nived O, Truedsson L, Valind S. Cardiovascular disease in systemic lupus erythematosus. A study of 75 patients form a defined population. Medicine (Baltimore). 1992 Jul;71(4):216–23.         [ Links ]

34. Tornos MP, Galve E, Pahissa A. Clinical considerations regarding infective Libman-Sacks endocarditis. Int J Cardiol. 1985 Apr;7(4):409–12.         [ Links ]

35. Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med. 1996 Nov 7;335(19):1424–30.         [ Links ]

36. Fluture A, Chaudhari S, Frishman WH. Valvular heart disease and systemic lupus erythematosus: therapeutic implications. Heart Dis. 2003;5(5):349–53.         [ Links ]

37. Plazak W, Gryga K, Milewski M, Podolec M, Kostkiewicz M, Podolec P, et al. Association of heart structure and function abnormalities with laboratory findings in patients with systemic lupus erythematosus. Lupus. 2011 Aug;20(9):936–44.         [ Links ]

38. Jensen-Urstad K, Svenungsson E, de Faire U, Silveira A, Witztum JL, Hamsten A, et al. Cardiac valvular abnormalities are frequent in systemic lupus erythematosus patients with manifest arterial disease. Lupus. 2002;11(11):744–52.         [ Links ]

39. Pons-Estel GJ, González LA, Zhang J, Burgos PI, Reveille JD, Vilá LM, et al. Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort. Rheumatology (Oxford). 2009 Jul;48(7):817–22.         [ Links ]

40. Comín-Colet J, Sánchez-Corral MA, Alegre-Sancho JJ, Valverde J, López-Gómez D, Sabaté X, et al. Complete heart block in an adult with systemic lupus erythematosus and recent onset of hydroxychloroquine therapy. Lupus. 2001;10(1):59–62.         [ Links ]

41. Lim L-T, Joshua F. Resolution of complete heart block after prednisolone in a patient with systemic lupus erythematosus. Lupus. 2005;14(7):561–3.         [ Links ]

42. Bilazarian SD, Taylor AJ, Brezinski D, Hochberg MC, Guarnieri T, Provost TT. High-grade atrioventricular heart block in an adult with systemic lupus erythematosus: the association of nuclear RNP (U1 RNP) antibodies, a case report, and review of the literature. Arthritis Rheum. 1989 Sep;32(9):1170–4.         [ Links ] 43. Fonseca E, Crespo M, Sobrino JA. Complete heart block in an adult with systemic lupus erythematosus. Lupus. 1994 Apr;3(2):129–31.         [ Links ]

44. Gómez-Barrado JJ, García-Rubira JC, Polo Ostáriz MA, Turégano Albarrán S. Complete atrioventricular block in a woman with systemic lupus erythematosus. Int J Cardiol. 2002 Mar;82(3):289–92.         [ Links ]

45. Martinez-Costa X, Ordi J, Barberá J, Selva A, Bosch J, Vilardell M. High grade atrioventricular heart block in 2 adults with systemic lupus erythematosus. J Rheumatol. 1991 Dec;18(12):1926–8.         [ Links ]

46. Szekanecz Z, Shoenfeld Y. Lupus and cardiovascular disease: the facts. Lupus. 2006;15(11 suppl):3-10.         [ Links ] 47. Aranow C, Ginzler EM. Epidemiology of cardiovascular disease in systemic lupus erythematosus. Lupus. 2000;9(3):166–9.         [ Links ] 48. Kalke S, Balakrishanan C, Mangat G, Mittal G, Kumar N, Joshi VR. Echocardiography in systemic lupus erythematosus. Lupus. 1998;7(8):540–4.         [ Links ]

49. Petri M. Detection of coronary artery disease and the role of traditional risk factors in the Hopkins Lupus Cohort. Lupus. 2000;9(3):170–5.         [ Links ]

50. Abu-Shakra M, Codish S, Zeller L, Wolak T, Sukenik S. Atherosclerotic cardiovascular disease in systemic lupus erythematosus: the Beer Sheva experience. Isr Med Assoc J. 2008 Jan;10(1):43–4.         [ Links ]

51. Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jansen-McWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1;145(5):408–15.         [ Links ]

52. Ward MM. Outcomes of hospitalizations for myocardial infarctions and cerebrovascular accidents in patients with systemic lupus erythematosus. Arthritis Rheum. 2004 Oct;50(10):3170–6.         [ Links ]

53. Urowitz M, Gladman D, Bruce I. Atherosclerosis and systemic lupus erythematosus. Curr Rheumatol Rep. 2000 Feb;2(1):19–23.         [ Links ] 54. Bessant R, Duncan R, Ambler G, Swanton J, Isenberg DA, Gordon C, et al. Prevalence of conventional and lupus-specific risk factors for cardiovascular disease in patients with systemic lupus erythematosus: A case-control study. Arthritis Rheum. 2006 Dec 15;55(6):892–9.         [ Links ]

55. Bruce IN, Urowitz MB, Gladman DD, Ibañez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum. 2003 Nov;48(11):3159–67.         [ Links ]

56. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, du Berger R, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 2001 Oct;44(10):2331–7.         [ Links ]

57. Brown JH, Doherty CC, Allen DC, Morton P. Fatal cardiac failure due to myocardial microthrombi in systemic lupus erythematosus. Br Med J (Clin Res Ed). 1988 May 28;296(6635):1505.         [ Links ]

58. Shome GP, Sakauchi M, Yamane K, Takemura H, Kashiwagi H. Ischemic heart disease in systemic lupus erythematosus. A retrospective study of 65 patients treated with prednisolone. Jpn J Med. 1989;28(5):599–603.         [ Links ] 59. Barker RA. The heart in systemic lupus erythematosus. BMJ. 1989 Jul 22;299(6693):245–7.         [ Links ]

60. Urowitz MB, Gladman D, Ibañez D, Fortin P, Sanchez- Guerrero J, Bae S, et al. Clinical manifestations and coronary artery disease risk factors at diagnosis of systemic lupus erythematosus: data from an international inception cohort. Lupus. 2007;16(9):731–5.         [ Links ]

61. Urowitz MB, Gladman D, Ibañez D, Fortin P, Sanchez- Guerrero J, Bae S, et al. Accumulation of coronary artery disease risk factors over three years: data from an international inception cohort. Arthritis Rheum. 2008 Feb 15;59(2):176–80.         [ Links ]

62. Urowitz MB, Gladman DD. Accelerated atheroma in lupus--background. Lupus. 2000 Jan;9(3):161–5.         [ Links ]

63. Ardoin SP, Sandborg C, Schanberg LE. Management of dyslipidemia in children and adolescents with systemic lupus erythematosus. Lupus. 2007;16(8):618–26.         [ Links ]

64. Frostegård J. Systemic lupus erythematosus and cardiovascular disease. Lupus. 2008 May;17(5):364–7.         [ Links ]

65. Hayata ALS, Borba EF, Bonfá E, Kochen JAL, Goldenstein- Schainberg C. The frequency of high/moderate lipoprotein risk factor for coronary artery disease is significant in juvenile-onset systemic lupus erythematosus. Lupus. 2005;14(8):613–7.         [ Links ]

66. Telles R, Lanna C, Ferreira G, Ribeiro A. Metabolic syndrome in patients with systemic lupus erythematosus: association with traditional risk factors for coronary heart disease and lupus characteristics. Lupus. 2010 Jun;19(7):803–9.         [ Links ]

67. Negrón AM, Molina MJ, Mayor AM, Rodríguez VE, Vilá LM. Factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico. Lupus. 2008 Apr;17(4):348–54.         [ Links ]

68. Sabio JM, Vargas-Hitos JA, Navarrete-Navarrete N, Mediavilla JD, Jiménez-Jáimez J, Díaz-Chamorro A, et al. Prevalence of and factors associated with hypertension in young and old women with systemic lupus erythematosus. J Rheumatol. 2011 Jun;38(6):1026–32.         [ Links ]

69. Bellomio V, Spindler A, Lucero E, Berman A, Sueldo R, Berman H, et al. Metabolic syndrome in Argentinean patients with systemic lupus erythematosus. Lupus. 2009 Oct;18(11):1019–25.         [ Links ]

70. Chung CP, Oeser A, Avalos I, Raggi P, Stein CM. Cardiovascular risk scores and the presence of subclinical coronary artery atherosclerosis in women with systemic lupus erythematosus. Lupus. 2006;15(9):562–9.         [ Links ]

71. Narshi CB, Giles IP, Rahman A. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus. 2011;20(1):5–13.         [ Links ]

72. Svenungsson E, Jensen-Urstad K, Heimbürger M, Silveira A, Hamsten A, de Faire U, et al. Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation. 2001 Oct 16;104(16):1887–93.         [ Links ]

73. Petri M. The lupus anticoagulant is a risk factor for myocardial infarction (but not atherosclerosis): Hopkins Lupus Cohort. Thromb Res. 2004 Jan;114(5-6):593–5.         [ Links ]

74. Vaarala O. Autoantibodies to modified LDLs and other phospholipid-protein complexes as markers of cardiovascular diseases. J Intern Med. 2000 Mar;247(3):381–4.         [ Links ]

75. Ribeiro GG, Bonfá E, Sasdeli Neto R, Abe J, Caparbo VF, Borba EF, et al. Premature coronary artery calcification is associated with disease duration and bone mineral density in young female systemic lupus erythematosus patients. Lupus. 2010;19(1):27–33.         [ Links ]

76. Kawai VK, Solus JF, Oeser A, Rho YH, Raggi P, Bian A, et al. Novel cardiovascular risk prediction models in patients with systemic lupus erythematosus. Lupus. 2011 Dec;20(14):1526–34.         [ Links ]

77. García-Carrasco M, Escárcega RO, Pérez-Terrón J, Ramírez A, Muñoz-Guarneros M, Beltrán A, et al. Lack of subclinical myocardial ischaemia in Mexican patients with systemic lupus erythematosus without traditional risk factors for coronary artery disease. Lupus. 2007;16(4):298–301.         [ Links ]

78. Nikpour M, Urowitz MB, Ibañez D, Gladman DD. Relationship between cardiac symptoms, myocardial perfusion defects and coronary angiography findings in systemic lupus erythematosus. Lupus. 2011 Mar;20(3):299–304.         [ Links ]

79. Korkmaz C, Cansu DU, Kaşifoğlu T. Myocardial infarction in young patients (< or =35 years of age) with systemic lupus erythematosus: a case report and clinical analysis of the literature. Lupus. 2007;16(4):289–97.         [ Links ]

80. Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. 2012 Jan;64(1):285–96.         [ Links ]

81. Roberts WC, High ST. The heart in systemic lupus erythematosus. Curr Probl Cardiol. 1999 Jan;24(1):1–56.         [ Links ]

82. Barnes E V, Narain S, Naranjo A, Shuster J, Segal MS, Sobel ES, et al. High sensitivity C-reactive protein in systemic lupus erythematosus: relation to disease activity, clinical presentation and implications for cardiovascular risk. Lupus. 2005;14(8):576–82.         [ Links ]

83. Sabio JM, Vargas-Hitos J, Zamora-Pasadas M, Mediavilla JD, Navarrete N, Ramirez A, et al. Metabolic syndrome is associated with increased arterial stiffness and biomarkers of subclinical atherosclerosis in patients with systemic lupus erythematosus. J Rheumatol. 2009 Oct;36(10):2204–11.         [ Links ]

84. Calvo-Alén J, Toloza SMA, Fernández M, Bastian HM, Fessler BJ, Roseman JM, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum. 2005 Jul;52(7):2060–8.         [ Links ]

85. Doria A, Shoenfeld Y, Wu R, Gambari PF, Puato M, Ghirardello A, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2003 Nov;62(11):1071–7.         [ Links ]

86. Wierzbicki AS. Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus. Lupus. 2000;9(3):194–201.         [ Links ]