Non-coronary cardiac manifestations of systemic lupus erythematosus in adults

INTRODUCTION — Cardiac disease is common among patients with systemic lupus erythematosus (SLE). Cardiac involvement in SLE can be summarized as follows:

●Valvular disease

●Pericardial disease

●Myocardial dysfunction

●Coronary artery disease

This topic review will focus on the non-coronary artery disease-related cardiac disorders associated with SLE in adults; coronary heart disease in SLE is presented separately (see "Coronary artery disease in systemic lupus erythematosus"). Overviews of the clinical manifestations of SLE in adults and children and a discussion of cardiac disease associated with SLE in children are also discussed elsewhere. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Cardiac' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

VALVULAR DISEASE

Clinical manifestations — Valvular involvement in patients with systemic lupus erythematosus (SLE) ranges from mitral valve prolapse to valvular vegetations consistent with nonbacterial thrombotic endocarditis (NBTE, Libman-Sacks endocarditis, verrucous endocarditis) [1]. Vegetations can be associated with valvular dysfunction, most commonly regurgitation. Most patients with vegetations are asymptomatic until embolization occurs (see "Nonbacterial thrombotic endocarditis", section on 'Clinical presentation and evaluation'). Unlike many other manifestations of SLE that are more frequent and severe during flares of disease activity, valvular lesions in SLE may occur at any time, and their presence does not correlate with disease activity.

Mitral valve prolapse appears to occur with increased frequency in patients with SLE, with estimates of it occurring in 21 percent of SLE cases versus 5.5 percent of controls in one study [2]. (See "Mitral valve prolapse: Clinical manifestations and diagnosis".)

In a report of 342 patients with SLE, 38 (11 percent) had verrucous lesions detected by transthoracic echocardiogram (TTE) [3]. Similar point prevalence rates (6 to 10 percent) have been noted in other studies using TTE [4]. As noted above, however, a higher prevalence (43 percent) has been noted when more sensitive transesophageal echocardiogram (TEE) is performed [4,5]. The clinical presentation, diagnosis, and management of NBTE is discussed in detail separately. (See "Nonbacterial thrombotic endocarditis".)

Valvular nodules, regurgitation, and NBTE appear to be more prevalent among patients with significantly elevated levels of antiphospholipid antibodies (aPL) [6-10].

A meta-analysis of 23 primary echocardiographic studies, including 1656 SLE patients (668 with and 988 without aPL) and 508 cases of heart valvular disease, found a greater than 3-fold significantly elevated risk of valvular disease and 3.5-fold elevated risk of NBTE among those with aPL, compared with those without aPL. The risk of valvular disease was highest for lupus anticoagulant (odds ratio [OR] 5.9, 95% CI 2.9-11.8) and immunoglobulin G (IgG) anticardiolipin antibodies (OR 5.6, 95% CI 3.5-9.0) [6]. Another meta-analysis of 21 studies, including 2163 SLE patients, of whom 23.3 percent had valvular lesions, also reported a statistically significant but relatively lower association between anticardiolipin antibodies positivity with valvular lesions (relative risk [RR] 1.6, 95% CI 1.1-2.2) [11]. Mitral valve lesions were the most common, and mitral regurgitation accounted for 19.7 percent of lesions. Other commonly found lesions were mitral valve prolapse (in 9.3 percent of patients) and tricuspid regurgitation (in 10.9 percent of patients). (See "Clinical manifestations of antiphospholipid syndrome", section on 'Cardiac involvement'.)

Diagnosis — Although serial echocardiographic examination in asymptomatic SLE patients is not warranted to detect the presence of valvular disease, a high index of suspicion should be present in patients with SLE, particularly in those with high titer aPL; an echocardiogram may be useful in those patients, in particular, if a murmur is detected. Cardiac auscultation should be performed at regular visits, followed by echocardiogram in patients with significant or changing murmurs or changing cardiac function. TEE may be necessary for detection of small valvular lesions [4]. (See "Nonbacterial thrombotic endocarditis", section on 'Echocardiography'.)

Blood cultures and echocardiography should be performed when a fever or a new murmur is noted in a patient with SLE. We do not typically perform screening echocardiography in the absence of symptoms or physical findings suggestive of valvular heart disease. Bacterial and other causes of NBTE, including cancer-associated marantic endocarditis and atypical infections such as Q fever, are also on the differential diagnosis [12,13].

Preventing bacterial endocarditis — The indications and regimens used for antimicrobial prophylaxis to prevent infective endocarditis after invasive or dental procedures are discussed elsewhere (see "Prevention of endocarditis: Antibiotic prophylaxis and other measures"). Patients with SLE and valve lesions who are immunosuppressed may represent a high-risk group for bacterial endocarditis that is not considered in the American College of Cardiology/American Heart Association guidelines (see "Prevention of endocarditis: Antibiotic prophylaxis and other measures"). We administer antibiotic prophylaxis before procedures associated with bacteremia for immunosuppressed SLE patients with known valve disease.

Therapy — The management of patients with SLE and NBTE usually consists of anticoagulation along with treatment of the underlying disease. A detailed discussion of the management of NBTE can be found elsewhere (see "Nonbacterial thrombotic endocarditis", section on 'Treatment'). Glucocorticoid and/or cytotoxic therapy as well as antiplatelet and anticoagulant therapy do not appear to reduce the size of valvular lesions, although there have been no prospective trials. Whether anticoagulation should be recommended for patients with aPL-associated vegetations who have never had any thromboembolic event is less clear and is discussed separately. (See "Management of antiphospholipid syndrome", section on 'Cardiac disease'.)

Valve replacement surgery or valve repair may be necessary for some patients who develop severe mitral or aortic valve regurgitation, or rarely for those with symptomatic stenotic lesions.

PERICARDIAL DISEASE — Pericardial involvement is the most common echocardiographic lesion in systemic lupus erythematosus (SLE) and is the most frequent cause of symptomatic cardiac disease [14]. Pericardial effusion occurs at some point in over one-half of patients, and pericarditis may precede the clinical signs of SLE.

Clinical manifestations and diagnosis — Pericardial disease may be asymptomatic and often found by echocardiography performed for some other reason [14]. Pericarditis, as with other types of serositis, most often occurs when SLE is active in other organs as well [15]. Large effusions and tamponade, as well as constrictive pericarditis, do occur in SLE [16,17].

Symptomatic pericarditis typically presents with pleuritic substernal chest pain, often with an audible rub on auscultation. There may also be signs of serositis at other sites (such as pleural effusion and ascites). Some patients may just have chest pain in the absence of the physical findings associated with pericarditis. The workup for pericarditis should include an evaluation for findings suggestive of active disease as well as consideration of other entities commonly seen in SLE, such as pleuritis, pulmonary embolism, and angina. Since progression to tamponade can occur in patients with SLE, patients with pericardial effusion should be closely watched for its development. The evaluation for suspected acute pericarditis and cardiac tamponade is discussed in detail separately. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Diagnostic evaluation' and "Cardiac tamponade".)

In clinical practice, measuring antinuclear antibodies (ANA), measuring complement components, or assaying for immune complexes in pericardial fluid is not helpful and just reflects the results of similar tests on peripheral blood samples. The pericardial fluid may contain ANA, phagocytic cells containing nuclei (lupus erythematosus [LE] cells), low complement levels, and immune complexes similar to those seen in SLE-related pleural effusions. The glucose concentration is normal, and the protein concentration is variable, being low with a transudate and elevated with an exudate. The pericardium may reveal foci of inflammatory lesions with immune complexes. There is usually a predominance of mononuclear cells, but scarring may be the primary finding in healed disease. Purulent pericarditis may occur, typically in an immunosuppressed, debilitated patient.

Pericardiocentesis may be indicated to exclude potentially life-threatening causes of pericarditis (eg, purulent, tuberculous, or neoplastic pericarditis) or to drain the fluid if there are signs of tamponade. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Pericardiocentesis and pericardial biopsy' and "Cardiac tamponade".)

In the absence of fever or a documented infection that could predispose to purulent pericarditis or signs of tamponade, we do not routinely perform pericardiocentesis in patients with SLE and pericarditis unless they do not respond to treatment and continue to have symptoms and a persistent pericardial effusion.

Course and treatment — Pericarditis resolves in the large majority of SLE patients [15]. It is often a manifestation of an SLE flare and thus hydroxychloroquine, with a short course of a nonsteroidal antiinflammatory drug (NSAID) or a medium- to low-dose glucocorticoid taper are first-line therapies [18]. (See "Acute pericarditis: Treatment and prognosis".)

Colchicine may reduce the risk of recurrence of idiopathic pericarditis [19], but the effectiveness of this agent in patients with SLE is uncertain. Use of colchicine may be tried in patients with SLE whose effusion does not respond to NSAIDs and/or glucocorticoids and, in a past case series, was effective within 1 to 30 days [20]. As colchicine can suppress the bone marrow, the complete blood count should be monitored closely in SLE patients taking colchicine (see "Acute pericarditis: Treatment and prognosis", section on 'Colchicine'). Patients with recurrent and severe pericarditis in the setting of active SLE often require immunosuppression with a drug such as azathioprine, mycophenolate mofetil, or belimumab [18]. (See "Recurrent pericarditis", section on 'Other immune therapy'.)

Percutaneous drainage with echocardiographic guidance is effective in treating cardiac tamponade; surgical drainage and pericardiectomy are rarely needed but may be necessary if there is a loculated effusion. (See "Cardiac tamponade".)

MYOCARDITIS — Myocarditis is a dangerous but often asymptomatic manifestation of systemic lupus erythematosus (SLE), with a prevalence of 8 to 25 percent [21,22]. Risk for myocarditis may be higher in Black populations compared with White populations or those of Hispanic ethnicity [21,23]. Global or patchy hypokinesis, not in a specific coronary artery distribution, may be an echocardiographic indication of myocarditis and is present in approximately 6 percent of patients with SLE [1].

Clinical manifestations and diagnosis — Myocarditis should be suspected with the following findings: tachycardia disproportionate to body temperature, electrocardiographic abnormalities (such as diffuse ST and T wave abnormalities), unexplained cardiomegaly, or symptoms of heart failure. The cardiomegaly may be associated with symptoms and signs of heart failure, conduction abnormalities, and/or arrhythmias [1]. Echocardiography may reveal abnormalities in both systolic and diastolic function of the left ventricle.

Acute myocarditis may accompany other acute manifestations of active SLE, particularly pericarditis. It can also occur subacutely. Among the many causes of cardiomyopathy, drug-induced (eg, due to high-dose cyclophosphamide, long-term antimalarials, phenothiazines) or comorbid disorders (eg, uremia or postpartum cardiomyopathy, viral myocarditis, or infiltrative diseases such as coexistent sarcoidosis or amyloidosis) should be excluded. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Cyclophosphamide' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Cardiotoxicity'.)

Cardiac magnetic resonance imaging (MRI) can help to establish the diagnosis of SLE myocarditis, and right heart catheterization with endomyocardial biopsy should be considered when it is not entirely clear that SLE is active and causing the myocarditis. Cardiac MRI in SLE patients with heart failure can help identify and differentiate acute myocarditis, dilated cardiomyopathy, myocardial infarction, vasculitis, and valvular heart disease. Late gadolinium enhancement is observed in areas of cardiac inflammation [24-28]. Endomyocardial biopsy can distinguish active myocarditis from fibrosis and other causes of cardiomyopathy, and to rule out other causes before proceeding to immunosuppressive therapy [29]. Histologic examination of myocarditis reveals infiltration of the myocardium with mononuclear cells. Inflammation may lead to fibrosis that may be manifested clinically as dilated cardiomyopathy.

In a study of the diagnostic role of cardiac MRI in detecting myocardial inflammation in SLE and its differentiation from viral myocarditis, 50 patients with suspected infective myocarditis and 25 active SLE patients with cardiac symptoms were assessed by coronary catheterization; endomyocardial biopsy; immunohistologic and polymerase chain reaction (PCR) analysis for viral deoxyribonucleic acid (DNA); and cardiac MRI [28]. When comparing patients with infective myocarditis with patients with active SLE who were found to have myocarditis on MRI, the patients with infective myocarditis were much more likely to be symptomatic than those with active SLE. Over half of all of the patients with myocarditis on MRI had confirmed myocarditis on endomyocardial biopsy. PCR was positive in almost all infective myocarditis patients, but was uncommon in SLE. Thus, due to the subclinical presentation of myocarditis in SLE patients, cardiac MRI may be useful in the diagnosis of SLE myocarditis.

Hydroxychloroquine is also associated with an idiosyncratic cardiotoxicity, and myocardial biopsy may be necessary to rule this out. The characteristic findings of hydroxychloroquine toxicity on light microscopy are diffuse myocyte vacuolization without myocarditis, and transmission electron microscopy demonstrates sarcoplasmic myelinoid and curvilinear inclusion bodies similar to Fabry disease [30,31]. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Neuromuscular toxicity'.)

Treatment of myocarditis — Treatment of lupus myocarditis has not been assessed in controlled trials. As SLE is often active, expert-based treatment guidelines suggest systemic glucocorticoids, intravenous cyclophosphamide or mycophenolate mofetil, usually with hydroxychloroquine, as first-line therapy for lupus myocarditis [18]. Improvement in systolic function has been noted in some patients treated with glucocorticoids, other immunosuppressants (eg, cyclophosphamide, azathioprine, or mycophenolate mofetil), or intravenous immune globulin (IVIG) [1,26,32]. Therapy for heart failure is also indicated, if present [1]. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

Cardiomyopathy with fibrosis is usually resistant to glucocorticoids and/or immunosuppressive drugs.

CONDUCTION ABNORMALITIES

Cardiac arrhythmias — Cardiac arrhythmias, which may represent sequelae of active or past myocarditis, have been reported to be highly prevalent among systemic lupus erythematosus (SLE) patients. The most common arrhythmias and electrocardiographic abnormalities observed in SLE populations are sinus tachycardia (18 percent), atrial fibrillation (9 percent), and QT prolongation (17 percent) [33].

●Past observations had suggested a relationship between the presence of anti-Ro/SSA antibodies and QT prolongation in adults. However, large studies have not confirmed this association [34,35].

●In a cross-sectional study of the large SLE International Collaborating Clinics (SLICC) cohort of 779 SLE patients, the prevalence of electrocardiogram (ECG) abnormalities was nonspecific ST-T changes (30.9 percent), possible left ventricular hypertrophy (5.4 percent), and supraventricular arrhythmias (1.3 percent) [34]. A QT interval (QTc) ≥440 msec was found in 15.3 percent, while a QTc ≥460 msec was found in 5.3 percent. Neither the specificity nor the level of anti-Ro/SSA was associated with QTc duration.

As hydroxychloroquine is a QTc-prolonging medication, guidelines for medications associated with potential for QTc prolongation should be followed (see "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management"). Baseline 12-lead ECG with QTc measurement prior to initiation of treatment, and repeated ECGs at intervals or when other QTc-prolonging medications are added are advisable in particular for patients at increased risk of torsades de pointes (female, advanced age, taking other QTc-prolonging drugs, underlying coronary artery disease, hypothyroidism, hypokalemia). It is not yet known what proportion of observed ECG abnormalities in past SLE cohort studies were attributable to hydroxychloroquine and, as patients with SLE do have increased risks of coronary and non-coronary heart disease, referral to a cardiologist for evaluation of ECG abnormalities is often indicated and helpful. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Cardiotoxicity'.)

First-degree heart block may be seen in patients with SLE, and they are at increased risk of higher degrees of heart block and arrhythmias (such as atrial fibrillation) [36]. Autopsy studies have revealed focal inflammatory cell infiltrates or, more often, fibrous scarring of the conduction system.

It should be noted that chronic resting tachycardia in SLE patients has been associated with increased disease activity, poor physical function, and possible subclinical serositis or pancarditis [37].

SUMMARY AND RECOMMENDATIONS

●Non-coronary cardiac manifestations are common in systemic lupus erythematosus (SLE) and should be high on the differential of presentation with tachycardia, electrocardiographic abnormalities, a cardiac murmur, chest pain or tightness, shortness of breath, palpitations, or pedal edema. Valvular disease, pericardial and myocardial inflammation, arrhythmias, and coronary heart disease occur at high rates in patients with SLE. (See 'Introduction' above.)

●Valvular involvement in patients with SLE ranges from mitral valve prolapse to valvular vegetations consistent with nonbacterial thrombotic endocarditis (NBTE). Although serial echocardiographic examination in asymptomatic SLE patients is not warranted to detect the presence of valvular disease, a high index of suspicion should be present in patients with SLE, particularly in those with high titer antiphospholipid antibodies (aPL), and an echocardiogram may be useful in those patients, in particular, if a murmur is detected (see 'Valvular disease' above). The management of NBTE is discussed in detail in a separate topic. (See "Nonbacterial thrombotic endocarditis", section on 'Treatment'.)

●Antibiotic prophylaxis is not recommended for most patients with SLE and valvular heart disease. However, patients with SLE and valve lesions who are immunosuppressed may represent a high-risk group not considered in the American College of Cardiology/American Heart Association guidelines. We administer antibiotic prophylaxis before procedures associated with bacteremia for immunosuppressed SLE patients with known valve disease. (See 'Preventing bacterial endocarditis' above.)

●Pericardial disease is a common manifestation of SLE and associated with SLE flares. Pericarditis, as with other types of serositis, most often occurs when SLE is active in other organs as well. Large effusions and tamponade can occur. Pericardiocentesis may be indicated to exclude potentially life-threatening causes of pericarditis (eg, purulent, tuberculous, or neoplastic pericarditis) or to drain the fluid if there are signs of tamponade. (See 'Pericardial disease' above.)

●Symptomatic acute pericarditis often responds to a nonsteroidal antiinflammatory drug (NSAID) or low-dose glucocorticoid (0.5 mg/kg/day tapered over two to three weeks). Colchicine may reduce the risk of recurrent pericarditis, and we suggest using colchicine (initial dose 1 to 2 mg orally for one day, then 0.5 mg twice daily, orally, for six months) (Grade 2B) (see 'Course and treatment' above). A reduction in the dose of colchicine is necessary if there is significant impairment in renal function. (See "Acute pericarditis: Treatment and prognosis", section on 'Colchicine'.)

●Myocarditis in SLE can be silent or cause resting tachycardia, cardiomegaly, heart failure, conduction abnormalities, and/or arrhythmias. Cardiac MRI is emerging as a useful technique for identifying SLE-related myocardial inflammation, but ultimately, many patients may need endomyocardial biopsy to establish the diagnosis and rule out other causes of myocarditis. Hydroxychloroquine is also associated with an idiosyncratic cardiotoxicity, usually after long-term use, and myocardial biopsy may be necessary to rule this out. (See 'Myocarditis' above.)

●For patients with lupus myocarditis, we suggest initial treatment with high-dose glucocorticoids (Grade 2C). A typical regimen is prednisone 1 mg/kg (or equivalent) intravenously or orally daily for three days tapered to oral prednisone. A glucocorticoid sparing agent such as mycophenolate mofetil, cyclophosphamide, or azathioprine is also typically initiated. For those with heart failure, this is accompanied by treatment for ventricular dysfunction. (See 'Treatment of myocarditis' above.)

●Cardiac arrhythmias have been reported to be highly prevalent among SLE patients. The most common arrhythmias and electrocardiographic abnormalities observed in SLE populations are sinus tachycardia, atrial fibrillation, and QT prolongation. (See 'Cardiac arrhythmias' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.