Epidemiology and Pathogenesis

Pericardial disease is the most common and first recognized cardiovascular manifestation of SLE. In 1924, Keefer and Felty¹ first described two lupus women with pericardial disease, one with a pericardial rub and another with fibrous adhesions at autopsy. Prevalence ranges from 16 to 100% have been reported (Table 32.1), depending on the type of diagnostic study and symptomatology of the patients. Echocardiographic evidence of pericardial abnormalities has been shown in 16 to 54%,^2–7 whereas autopsy findings of pericardial disease have been reported in up to 100% of SLE patients.^8–11 While the majority of lupus patients with pericardial effusions are asymptomatic, approximately 25% will develop symptomatic pericarditis during their disease course.¹² Older age of disease onset¹³ and the presence of SSB/La autoantibodies in adults^2,14 are risk factors that have been associated with pericardial disease. Pericardial disease may also be seen with drug-induced SLE.

TABLE 32.1 CARDIOVASCULAR DISEASES IN SYSTEMIC LUPUS ERYTHEMATOSUS

Immunopathology of the pericardium¹⁵ and pericardial fluid¹⁶ have revealed immune complexes of IgG, IgM, C3, and C1q, confirming the inflammatory pathogenesis. Pathology of pericardial disease has changed with the advent of corticosteroids. Focal or diffuse active fibrinous changes were observed prior to corticosteroids,¹⁷ and healed fibrous lesions predominate since the introduction of steroid therapy.⁸

Clinical Manifestations and Diagnosis

The symptomatology of acute pericarditis is not specific for SLE. Patients can experience substernal or precordial chest pain that is positional in nature. Symptoms are worse with inspiration, supine position, coughing, or swallowing, and are relieved with sitting up or bending forward. Fever, dyspnea, and tachycardia are other common symptoms. Pericarditis may be associated with generalized serositis, typically pleuritis,¹⁸ or inflammation in other organs.¹⁹

On auscultation, diminished heart sounds and a pericardial friction rub may be heard. This high-pitched scratchy sound is variable, and is best heard with the patient leaning forward at end-expiration. Hypotension, elevated jugular venous distension (JVD), hepatic congestion, and pulsus paradoxus (a drop in systolic blood pressure of >10 mmHg during inspiration) can be seen with pericardial tamponade.

Tamponade is an unusual complication of pericardial effusions in SLE patients, and may be secondary to an acute accumulation of small or moderate amounts of pericardial fluid or subacute accumulation of large amounts of fluid. In large SLE patient series, 20 reports of tamponade were seen, with an estimated rate of 2.5%.⁵ Many other case reports have been cited in the literature.²⁰ Tamponade may be the initial presenting symptom of SLE or may occur throughout the disease course. Drug-induced pericardial tamponade has occurred with procainamide,²¹ isoniazid,²² hydralazine,²³ and carbamazepine.²⁴

Constrictive pericarditis is rarely associated with SLE. Chronic inflammation and subsequent thickening of the pericardium lead to impairment of diastolic filling and ventricular function. Patients may have a third heart sound (pericardial knock) and Kussmaul’s sign (persistent elevation of venous pressure during inspiration) along with hepatic congestion, ascites, and leg edema. Constrictive pericarditis has also been associated with procainamide use.^15,25

Septic or purulent pericarditis is a rare complication in SLE patients. All reported cases occurred in patients taking steroids.¹² Staphylococcus aureus,²⁶ Candida,²⁷ and tuberculosis have been identified in septic pericarditis. Therefore, infection should be part of the differential diagnosis in immunosuppressed patients with SLE who present with acute pericarditis.

Electrocardiographic (EKG) findings reveal a classic PR interval depression with diffuse concave ST segment elevation (Fig. 32.1). Tachyarrhythmias (atrial fibrillation and flutter) and rarely bradyarrhythmias can occur. Electrical alternans, with beat-to-beat irregularity, and reduced QRS voltage can occur with large pericardial effusions and tamponade. The chest radiograph (CXR) may be normal or reveal a classic “water-bottle” cardiac silhouette (Fig. 32.2), pericardial fat lines, or pleural effusions.

Fig. 32.1 Electrocardiogram of acute pericarditis showing sinus tachycardia, diffuse ST elevation, and PR depression in lead II, aVF, and lateral precordial leads.

(Courtesy of John C. Bailey, MD, Indiana University School of Medicine, Indianapolis, IN.)

Fig. 32.2 Chest radiograph (AP view) of acute pericarditis showing enlarged cardiac silhouette with both pericardial and pleural effusions.

Echocardiography is the diagnostic modality of choice and is the best test to evaluate for pericardial tamponade. Pericardial effusions are recorded as a relatively echo-free space between the pericardium and ventricular epicardium. With large effusions, the heart may swing freely within the pericardial sac. Pericardial tamponade may reveal right ventricular diastolic collapse and paradoxical septal motion. Pericardial thickening and calcifications are seen in constrictive pericarditis. Computed tomography (CT) and magnetic resonance imaging (MRI) are better than echocardiography in identifying loculated effusions, but will also reveal the pericardial thickening seen on echocardiography in chronic disease and constrictive pericarditis.

The pericardial fluid in patients with SLE-related pericarditis is generally straw-colored, but may be serosanguinous or hemorrhagic. The fluid is exudative with elevated protein, normal to low glucose levels, and elevated white blood cell count with a predominance of polymorphonuclear cells. Autoantibodies (antinuclear [ANA] and double-stranded DNA [dsDNA]) and LE cells have been detected in the pericardial fluid of some patients with SLE.²⁸ While ANA-positive pericardial fluid may be suggestive of SLE, it is not specific, and has been seen in other autoimmune diseases (rheumatoid arthritis), infections (tuberculosis), and malignancies.²⁸

The diagnosis of pericarditis in lupus patients is often a clinical one based on typical signs and symptoms since it may occur without a detectable effusion on echocardiography or an abnormal EKG. Careful consideration should also be given to other diagnostic possibilities, including pulmonary embolus, myocardial infarction (MI), aortic dissection, purulent pericarditis, and pneumonia.

Treatment

Asymptomatic and hemodynamically stable patients with pericardial effusions are generally not treated. Therapy of symptomatic disease varies upon severity of symptoms. Mild pericarditis often responds to nonsteroidal anti-inflammatory agents (NSAIDs). Corticosteroid therapy (prednisone 20 to 80mg/day or 0.5 to 1.0mg/kg/day) is used for severe or refractory pericarditis and pericardial tamponade. Improvements in symptoms, ventricular function, and tamponade have been reported with the use of intravenous methylprednisolone, immunosuppressive agents, and immunomodulating agents, such as intravenous immunoglobulin (IVIg).²⁹ Pericardiocentesis is a necessary intervention for pericardial tamponade, suspicion of septic pericarditis, or in symptomatic patients refractory to medical treatment. A pericardial window may also be required. In patients with chronic disease and constrictive pericarditis, pericardial stripping or pericardiectomy may be performed.

Epidemiology and Pathogenesis

Cardiac rhythm and conduction abnormalities occur in 10 to 75% of SLE patients^8,30–32 (Table 32.1). This variability in prevalence is a consequence of different case definitions. Sinus tachycardia is the most common arrhythmia; however, bradycardia, atrial arrhythmias, and first- and second-degree atrioventricular (AV) heart block also occur. Third-degree or complete heart block is rare in adult lupus patients. Cardiac autonomic dysfunction is also a recognized complication of SLE.^30,33

Complete heart block and other conduction abnormalities are rare as a presenting manifestation, but more commonly occur later in the disease course.³⁴ The major difficulty is attributing conduction abnormalities to SLE alone, as other more common causes such as atherosclerotic disease, electrolyte disturbances, and thyroid dysfunction are commonly seen in SLE patients. When conduction abnormalities are related to lupus,³⁵ it is commonly associated with other disease manifestations such as pericarditis, myocarditis, and antibodies to ribonucleoprotein (U1-RNP)^36,37 and SSA/Ro.³² Adult complete heart block has been associated with antimalarial drug-induced cardiotoxicity³⁸; only 13 case reports of complete heart block without concomitant hydroxychloroquine use have been reported.³⁷

When conduction abnormalities are believed to be SLE related, immune-mediated injury to conduction tissues and small vessels of the myocardium are felt to be the underlying pathogenesis. Pathologic specimens have revealed focal degeneration and fibrosis of the sinus node, AV node, and AV bundles, as well as necrotizing arteritis and occlusion of the central sinus node artery.^8,39 This chronic inflammation and fibrosis may lead to irreversible defects in the conduction system.

Neonatal conduction abnormalities and congenital heart block (CHB) are well-recognized complications of neonatal lupus. CHB in infants (before or after birth) is associated with maternal autoantibodies to SSA/Ro and SSB/La in more than 85% of cases, independent of whether the mother has evidence of SLE.⁴⁰ Approximately 2 to 3% of anti-SSA/Ro–positive mothers will have a child with CHB.⁴¹ Maternal IgG antibody–mediated CHB is most often detected at 18 to 24 weeks of gestation.⁴² Fetuses of mothers with SSA/Ro and SSB/La autoantibodies should be followed by maternal-fetal specialists and monitored by serial fetal echocardiograms. Dexamethasone (fluorinated corticosteroid), IVIg, plasmapheresis, and in utero cardiac pacing are used when evidence of arrhythmias or heart failure is detected. Mortality rates are close to 20%, with 60% of children requiring pacemakers.⁴²

Clinical Manifestations and Diagnosis

Patients may experience a spectrum of symptoms from fatigue, weakness, and palpitations to heart failure and syncope. Asymptomatic abnormalities may be found coincidentally on an EKG, revealing arrhythmias or conduction abnormalities. Etiologies other than SLE (ischemia, thyroid dysfunction, electrolyte imbalance, and medications) must be investigated.

Treatment

Asymptomatic tachyarrythmias and first- or second-degree AV block do not require intervention and may be observed, assuming that other nonlupus causes have been investigated and treated. Third-degree and any conduction abnormality that results in hemodynamic instability requires intervention with medical therapy, such as antiarrhythmic medications or pacemaker placement. Corticosteroid therapy has successfully treated conduction blocks in a small number of case reports.³⁵ One should keep in mind the association of drug-induced conduction abnormalities, such as antimalarials, and the offending medication should be discontinued.

Epidemiology and Pathogenesis

Myocardial abnormalities are observed in 5 to 57% of patients^7,43–45 (Table 32.1), of which 10% are clinically apparent.^18,43,46 Subclinical myocarditis has been reported in as many as 57% of autopsy series from the 1950s and 1960s.⁴³ With the widespread use of corticosteroids, prevalence of myocarditis on autopsy has decreased to 7%. Myocarditis may progress to ventricular dysfunction, cardiomyopathy, and heart failure.⁴⁶

The majority of myocardial abnormalities are due to lupus-related comorbidities such as ischemic heart disease, hypertension, renal failure, valvular disease, and medication toxicity. A 5-year prospective study demonstrated progressive abnormalities of systolic and diastolic left ventricular function in lupus patients with coexisting hypertension and coronary artery disease.⁴⁷ The degree to which myocardial dysfunction is due to myocarditis or direct immune-mediated damage to myocardium is unknown.

Abnormal cardiac hemodynamics on catheterization have been described in lupus patients without evidence of cardiac disease. Strauer and colleagues revealed increased biventricular end-diastolic pressures, decreased cardiac output, decreased cardiac contractility, decreased ejection fraction, increased wall stiffness, and reduction of coronary artery reserve.⁴⁸ Del Rio and colleagues,⁴⁹ described left ventricular dysfunction with higher heart rates, shortened left ventricular ejection time, and a prolonged pre-ejection period when compared to controls. These abnormalities were independent of age, disease duration, hypertension, corticosteroid use, and renal involvement, suggesting disease-related chronic inflammation as the cause. Ventricular dysfunction has also been associated with elevated anti-DNA antibody titers, suggesting a correlation with disease activity.

The pathogenesis of myocardial dysfunction is an immune-complex mediated process, with complement deposition and cytokine activation within the myocardial blood vessels, and to a lesser degree, myocardial tissue.^50,51 Small foci of interstitial plasma cells and lymphocytes can be seen within the myocardial tissue, but diffuse inflammation is uncommon.^8,12 Subsequent necrosis and fibrosis of myocytes leads to myocardial depression and conduction system abnormalities. In corticosteroid-treated patients, small foci of patchy myocardial fibrosis are observed, likely representing healed myocarditis.⁸ Circulating autoantibodies have also been hypothesized to play a role in the pathogenesis of myocardial dysfunction in SLE. Antimyocardial⁵² and anti-SSA/Ro³² autoantibodies have been associated with myocarditis. Borenstein and colleagues reported an association between the presence of anti–U1-RNP autoantibodies, myositis, and myocarditis in five SLE patients, suggesting a generalized inflammatory myopathic process.⁵³

Clinical Manifestations and Diagnosis

Clinical signs and symptoms are not specific for SLE, but are based on the severity of myocardial dysfunction. Lupus patients with myocarditis may be asymptomatic, or present with fever, chest pain, dyspnea, palpitations, and tachycardia out of proportion to fever. Presentation may be acute or chronically progressive with ultimate heart failure. Patients may experience fatigue, cough, orthopnea, paroxysmal nocturnal dyspnea, and signs of congestive heart failure. A cardiac murmur, third heart sound, or gallop rhythm may be auscultated, with irregular heart rate, displaced apex, elevated jugular venous distension (JVD), and lower extremity edema. Elevation of creatine kinase (CK) and troponin has not consistently correlated with myocardial involvement. Myocardial dysfunction may accompany other manifestations of SLE, specifically pericarditis. However, myocarditis is an unusual initial manifestation of SLE.⁵⁴

Electrocardiograms reveal nonspecific ST segment changes, premature atrial or ventricular contractions, arrhythmias, and conduction abnormalities. Asymptomatic patients may first be discovered on an EKG evaluation performed for other reasons. Chest radiographs may be normal or have evidence of cardiomegaly, with or without pulmonary edema.

Echocardiographic findings are nonspecific for lupus myocardial dysfunction, but are helpful in assessing cardiac function. Decreased ejection fraction, increased chamber size, prolonged relaxation time, decreased deceleration of early diastole, and decreased E/A ratio (filling of left ventricle in early and late diastole) have been observed in lupus patients.⁴³ Cardiac catheterization has revealed abnormalities previously described by Strauer and colleagues,⁴⁸ and should be considered to rule out coronary heart disease (CHD), particularly in patients with chest pain or cardiovascular risk factors.

New imaging techniques have suggested the ability to detect myocardial injury; unfortunately the number of patients evaluated is small and the findings are not specific for lupus. Cardiac MRI has revealed higher T2 relaxation times, suggestive of myocardial edema, in active lupus patients when compared to asymptomatic lupus patients and controls.⁵⁵ Diffuse accumulation of gallium-67 citrate scintigraphy has been reported in a lupus patient with clinical evidence of myocarditis.⁵⁶ Indium-111 antimyosin Fab imaging in lupus patients has suggested more widespread disease than initially described by echocardiography.⁵⁷

Endomyocardial biopsy reveals fibrous thickening of arterial walls with luminal narrowing and IgG deposits in perivascular areas; foci of plasma cells, lymphocytes, and neutrophils in the myocardium; and myocardial fibrinoid necrosis, fibrosis, and scarring.^{8,12,43,50,51,58,59} These findings are suggestive of lupus myocarditis in the appropriate clinical setting, but are not specific. The American College of Cardiology/American Heart Association (ACC/AHA)⁶⁰ states that “endomyocardial biopsy can be useful in patients presenting with heart failure when a specific diagnosis is suspected that would influence therapy” and that “endomyocardial biopsy should not be performed in the routine evaluation of patients with heart failure.” The sensitivity and specificity of endomyocardial biopsy in lupus is unclear. Ardehali and colleagues recently evaluated the utility of diagnosis by endomyocardial biopsy in patients with unexplained cardiomyopathy.⁶¹ The sensitivity of endomyocardial biopsy compared to clinical diagnosis was 100% versus 66%, with equal specificities (86% vs. 87%). Seven patients were diagnosed with SLE, all of whom were diagnosed based on other clinical manifestations without endomyocardial biopsy.

Prior to making a diagnosis of SLE-related inflammatory myocardial disease, other non-SLE etiologies must be investigated. Ischemic heart disease, which is the leading cause of cardiomyopathy and myocardial dysfunction, occurs at increased frequency in SLE patients. Renal disease and hypertension, two conditions common to SLE patients, also contribute to myocardial dysfunction. Infectious etiologies, both viral and bacterial, must be considered in a new diagnosis of myocarditis. Finally, treatment-related cardiotoxicity from cyclophosphamide and antimalarial medications must also be considered.

Antimalarial medications, chloroquine phosphate (CQ) and especially hydroxychloroquine sulfate (HCQ), have become a part of standard therapy in SLE. Rare but potentially serious toxicities have been reported, including myopathy, neuropathy, and retinotoxicity. Cardiotoxicity from both CQ and HCQ has been reported in 25 cases in the English-language literature to date^38,62,63; however, less than 50% of these are biopsy proven. Systolic and diastolic dysfunction, as well as conduction abnormalities (first-degree AV block, right bundle branch block, left bundle branch block, and complete heart block) have been reported. Antimalarial drug-induced cardiotoxicity is a diagnosis of exclusion; however, endomyocardial biopsy may be diagnostic for it. Endomyocardial histology reveals large secondary lysosomes, and myeloid and curvilinear bodies (lipid-rich structures representing abnormal lysosomes), with variable myofiber atrophy and necrosis^62–64 (Figs. 32.3 and 32.4). The majority of cases are older women with long duration of antimalarial therapy; however, identification of risk factors is difficult given the small number of case reports.⁶³ This diagnosis should be considered in the clinical scenario of myocardial dysfunction, past or concurrent use of CQ or HCQ, and endomyocardial biopsy.

Fig. 32.3 Light microscopy of endomyocardial biopsy tissue for hydroxychloroquine-induced cardiotoxicity. A, Diffusely enlarged and vacuolated myocytes (paraffin-embedded, hematoxylin-eosin stain, magnification x180). B, Extensive sarcoplasmic accumulation of darkly staining material (plastic-embedded toluidine blue stain, magnification x540).

(From Keating RJ, Bhatia S, Amin S, et al. Hydroxychloroquine-induced cardiotoxicity in a 39-year-old woman with systemic lupus erythematosus and systolic dysfunction. J Am Soc Echocardiogr 2005;18:981.)

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