AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Libman-Sacks (verrucous) endocarditis is the most characteristic cardiac manifestation of the autoimmune disease systemic lupus erythematosus (see Systemic Lupus Erythematosus for more information). Libman and Sacks first published a description of these atypical, sterile, verrucous vegetations in 1924.¹

Postmortem studies describe mulberrylike clusters of verrucae on the ventricular surface of the posterior mitral leaflet, often with adherence of the mitral leaflet and chordae to the mural endocardium. The lesions typically consist of accumulations of immune complexes and mononuclear cells. The condition is not always recognized on echocardiographic images. With the introduction of steroid therapy for systemic lupus erythematosus, improved longevity of patients appears to have changed the spectrum of valvular disease.

Valvular abnormalities occur as masses (classic Libman-Sacks vegetations; see Media file 1), diffuse leaflet thickening, valvular regurgitation, and, infrequently, stenosis. Valvular regurgitation is noted most commonly in patients with leaflet thickening, which is thought to represent the chronic healed phase of disease. The left-sided valves are involved most often.

Lesions similar to those described by Libman and Sacks also occur in association with primary or secondary antiphospholipid syndrome. The role of these autoantibodies in the pathogenesis of Libman-Sacks endocarditis is disputed.

Lesions are usually clinically silent. Heart failure, valvular dysfunction, valve replacement, embolic phenomena, and secondary infective endocarditis can complicate valvular abnormalities.

Pathophysiology

Libman-Sacks endocarditis most commonly involves mitral and aortic valves. However, all 4 cardiac valves and the endocardial surfaces can be involved.

Valvular abnormalities are often clinically silent, without significant valvular dysfunction. Valvular regurgitation is more common than stenosis, which is rare. Valvular dysfunction can result in cardiac failure. Embolic phenomena and secondary infective endocarditis are uncommon but can result in neurological and systemic complications.

Frequency

International

Valvular abnormalities are commonly detected in patients with lupus. The characteristic Libman-Sacks vegetations are reported postmortem in approximately 50% of fatal lupus cases. Current echocardiographic studies reveal valvular abnormalities in 28-74% of patients, with valve masses in 4-43% of patients with systemic lupus erythematosus. Higher rates are generally detected with transesophageal imaging and in subjects with antiphospholipid antibodies (41% with masses), although this observation is not universal.

One cohort study found that Libman-Sacks endocarditis was found in 11% of patients with lupus.² Pure mitral regurgitation was the most common valvular abnormality, followed by aortic regurgitation, combined mitral stenosis and regurgitation, and combined aortic stenosis and regurgitation. At baseline, Libman-Sacks endocarditis was significantly associated with underlying lupus disease activity. During the follow-up echocardiograph, patients with previous valvular lesions had worsened valve function, and more patients developed new valve lesions.

Patients with valve masses often have coexistent leaflet thickening, which is noted in 71% of patients with valve masses. Echocardiography detects valvular thickening in 19-52% of patients with systemic lupus erythematosus.

In older patients with a longer mean duration of systemic lupus erythematosus and a larger cumulative dose of steroids, valves that appear to be thickened and rigid occur more commonly than verrucous vegetations. The prevalence of regurgitation in patients with thickened valve leaflets has been reported to be as high as 73%.

The prevalence of valvular abnormalities detected during echocardiography in patients with primary antiphospholipid syndrome has been reported at 30-32%. Abnormal echocardiographic findings are most common in those with peripheral arterial thromboses, noted in up to 64% of patients. Leaflet thickening is the most frequent abnormality, noted in 10-24% of patients. Vegetationlike masses occur in 6-10% of patients.

Mortality/Morbidity

• Mortality is undefined. Patients with systemic lupus erythematosus have an increased mortality rate compared with the general population. Cardiovascular mortality is ranked third in these patients but includes a wide spectrum of pathology.
• The combined rate of heart failure, valvular replacement, thromboembolism, and secondary infective endocarditis has been reported to be as high as 22% in lupus patients with valvular disease, compared with 8% of patients without valvular disease. Most patients do not have clinically significant valvular dysfunction. Regurgitation is noted on echocardiography images in 25-61% of lupus patients and in 10-24% of patients with primary antiphospholipid syndrome. The prevalence of moderate or severe regurgitation has been reported in 0-12% (severe in 3%, moderate in 9%) of patients with antiphospholipid syndrome and 4-26% of lupus patients. The reported need for valve replacement varies from 1-8% of cases.
  
  The occurrence of clinically significant embolic phenomena is thought to be low. Although stroke rates are higher in patients with lupus and antiphospholipid syndrome, multifactorial etiologies for neurological events are often present, making the specific contribution of valvular abnormalities difficult to determine. The likely prevalence of secondary infective endocarditis is low, but it has not been widely reported. Potential contributing factors to infective endocarditis are systemic lupus erythematosus, medications prescribed for lupus, and underlying valvular abnormalities.

Race

US statistics show systemic lupus erythematosus to be more prevalent in black and Hispanic women.

Sex

Systemic lupus erythematosus and primary antiphospholipid syndrome occur 5-9 times more often in women; therefore, patients with cardiac valvular lesions are generally young women.

CLINICAL

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History

• Persons with Libman-Sacks endocarditis are usually asymptomatic.
• Cardiac failure might develop secondary to valvular dysfunction (most commonly mitral regurgitation), leading to dyspnea, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, and lethargy.
• Cerebrovascular embolism might occur, leading to symptoms of cerebral ischemia, including focal weakness and/or numbness, visual loss, dysphasia, dysarthria, dysphagia, and memory loss.
• Rarely, systemic thromboembolism can result in a wide spectrum of symptoms, including pain, coldness and numbness of the peripheries, or acute abdominal syndromes with pain and vomiting.
• Secondary infective endocarditis might manifest as fever, weight loss, night sweats, lethargy, and chest pain. These symptoms can be difficult to distinguish from underlying systemic lupus erythematosus disease activity.
• Symptoms of systemic lupus erythematosus might be noted, including a history of rash, arthritis (joint pain and swelling), and sweating.
• Features of antiphospholipid syndrome might be noted in the history, including recurrent miscarriage, arterial thromboses, venous thromboses, and/or thrombocytopenia.
• • Patients may report pain, numbness and discoloration of the extremities, focal neurological symptoms (eg, focal weakness and/or numbness, visual loss, dysphasia, dysarthria, dysphagia, memory loss), and ischemic chest pain with arterial thromboses.
  • Venous thromboembolism might result in peripheral swelling, pleuritic chest pain, dyspnea, and hemoptysis. Neurological symptoms due to cerebral ischemia can also occur in the event of a paradoxical embolus.

Physical

• Physical examination findings can be normal.
• The following cardiac murmurs might be heard:
• • Ejection systolic murmur (crescendo decrescendo): This is most commonly the result of a hyperdynamic state due to associated conditions and can indicate aortic valve thickening with or without stenosis.
  • Holosystolic murmur of mitral regurgitation or tricuspid regurgitation
  • Early diastolic murmur of aortic regurgitation, with or without an Austin-Flint murmur
  • Middiastolic, rumbling murmur of mitral stenosis
• Other valvular dysfunction (eg, pulmonary stenosis or regurgitation, tricuspid stenosis) might occur, but only rarely is this due to Libman-Sacks endocarditis.
• The following signs of ventricular enlargement and cardiac failure might be noted:
• • Tachypnea and cyanosis
  • Pulse (plateau pulse, low-volume pulse, pulsus alternans)
  • Jugular venous distension
  • Displaced apex beat
  • Third and/or fourth heart sounds
  • Pulmonary rales
  • Congestive hepatomegaly
  • Sacral and peripheral edema
• A focal neurological deficit secondary to embolic phenomena or thrombosis with or without the antiphospholipid syndrome might be noted.
• Signs due to underlying systemic lupus erythematosus might be present, including rash and joint swelling.

Causes

• The pathogenesis is unknown.
• Antiphospholipid antibodies are frequently associated with valvular abnormalities.
• • These autoimmune antibodies are directed against negatively charged phospholipids present in endothelial cell membranes.
  • Immunohistological studies suggest a pathogenetic role of these autoimmune antibodies. However, a similar prevalence and severity of valvular disease has been described in lupus patients without these antibodies; their presence does not seem to be required.
• Impaired antithrombotic mechanisms present in patients with antiphospholipid syndrome also might be implicated in the pathogenesis of thrombosis and valvular lesions. Areas of endothelial damage caused by turbulence and the jet effect on the left side of the heart are potential sites of platelet and fibrin deposition.
• Steroid therapy is implicated in the modification of the nature of valvular abnormalities and in the dysfunction observed in patients with systemic lupus erythematosus.
• • With the introduction of steroid therapy, valvular thickening and regurgitation appear to occur more commonly, with histologically active lesions identified less frequently.
  • Data are circumstantial and might reflect improved longevity of patients. Firm conclusions cannot be made.

DIFFERENTIALS

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Other Problems to be Considered

Degenerative valvular disease
Fibroelastoma
Rheumatic valvular disease
Lambl excrescences (normal variant): These are filiform strands that originate at valve closure sites. They are thought to be normal variants, but some reports have proposed embolic potential.³

WORKUP

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Lab Studies

Lab studies to test for Libman-Sacks Endocarditis should include the following:

• Blood cultures: Infective endocarditis should be excluded.
• Complete blood cell count
• • Neutrophilia might indicate infection.
  • Coexistent anemia can be present.
• Antiphospholipid antibodies, including anticardiolipin antibody, lupus anticoagulant, VDRL, and Russell viper venom test
• Coagulation profile with prothrombin time and activated partial thromboplastin time
• Antinuclear antibody with or without antiextractable nuclear antigens or anti–beta2-glycoprotein
• Anti-DNA antibody assay (double-stranded): A workup for systemic lupus erythematosus might be indicated.

Imaging Studies

• Types of echocardiography
• • Whether to use transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) depends on the clinical scenario.
  • Transthoracic echocardiography is most appropriate for the initial evaluation of cardiac murmurs and quantification of left atrial volume and left ventricular volumes, mass, and contractile function.
  • One study compared TTE with TEE for the diagnosis of Libman-Sacks endocarditis.⁴ Using TEE as the standard, TTE demonstrated a low sensitivity (63% overall, 11% for valve vegetations), low specificity (58%), low negative predictive value (40%), and a moderate positive predictive value (78%) for detection of Libman-Sacks endocarditis. Thus, TEE should be performed when the TTE is nondiagnostic or when the pretest probability is high.
• Results of echocardiography
• • Irregular borders, heterogeneous echodensity, and no independent motion characterize the masses (ie, verrucous vegetations) on the cardiac valves and endocardium. The masses are usually small and sessile, but they can be as large as 10 mm. The basal and mid portions of the mitral and aortic valves are involved most commonly.
  • Diffuse leaflet thickening of the mitral and aortic valves or focal leaflet thickening of the midbasal leaflet can be observed.
  • Acoustic shadowing suggesting calcification is possible but uncommon.
  • Valvular regurgitation can be seen.
  • Valvular stenosis may be present but is rare.
  • Left ventricular enlargement and/or dysfunction can be observed.
  • Coexistent cardiac complications of systemic lupus erythematosus may include pericardial effusion or thickening, left ventricular hypertrophy (due to hypertension), left ventricular dilatation, left ventricular segmental dysfunction, left ventricular global dysfunction, or elevated pulmonary artery pressure.
  • Transesophageal echocardiography offers superior resolution of cardiac valves and helps detect valvular lesions (especially left-sided valves) with greater sensitivity and specificity than transthoracic echocardiography.
• Chest radiograph
• • Cardiomegaly and pulmonary congestion might be noted.
  • Calcified masses and valvular tissue are possible but are rare.

Other Tests

• Cardiac catheterization
• • Perform coronary angiography if cardiac ischemia is suggested and if valve replacement surgery is indicated because systemic lupus erythematosus is associated with premature atherosclerotic coronary artery disease and coronary vasculitis. However, if large aortic lesions are present, noninvasive coronary artery evaluation (such as CT angiography) may be indicated because catheterization may cause embolization.
  • Left-sided pressure tracings, ventriculography, and aortography might yield additional information regarding valvular dysfunction and left ventricular function.
  • Right-sided heart catheterization is useful to determine pulmonary artery pressure and pulmonary vascular resistance because both cardiac and pulmonary pathology can occur with lupus. Use caution because the severity of valvular dysfunction in the presence of pulmonary disease might be overestimated.

Histologic Findings

The different stages of Libman-Sacks endocarditis have been described as active, active and healed, and healed lesions. Active verrucae consist of clumps of fibrin on and within the valvular leaflet tissue, which is focally necrotic, with plasma cells and lymphocytes. Combined active and healed lesions contain vascularized, fibrous tissue adjacent to fibrinous and necrotic areas. Healed lesions consist of dense, vascularized, fibrous tissue.

Histologic examinations of patients with lupus who undergo valve replacement often show the latter 2 stages, with the excised, dysfunctional leaflet tissue being fibrotic, retracted, and partially calcified with fibrinous deposits. Overlying thrombi have also been reported on valves examined at operation. Hematoxylin bodies can also be present.

Immunoglobulin and complement deposits have been identified subendothelially and in the core of vegetations.

TREATMENT

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Medical Care

• No specific therapy is indicated for Libman-Sacks endocarditis.
• The use of corticosteroids and/or cytotoxic agents for acute enlarging vegetations is controversial. Furthermore, steroid usage is implicated in the formation of leaflet thickening and valvular dysfunction. However, a recent prospective study of 56 patients with primary antiphospholipid syndrome observed that 17 patients (36%) developed new cardiac abnormalities at the 5-year follow-up. New appearances of cardiac involvement were significantly related to high immunoglobulin-G levels and anticardiolipin antibody titers, suggesting that lowering these titers with immune-modulating therapy may prevent the development of cardiac lesions.
• Antibiotic prophylaxis is recommended for prophylaxis of secondary infective endocarditis during procedures precipitating bacteremia (eg, dental work, colonoscopy, rigid bronchoscopy, cystoscopy, colonic surgery). However, these guidelines are not well based on evidence in the case of Libman-Sacks valvular disease.
• Anticoagulation with warfarin is often indicated for atrial fibrillation, mitral stenosis, mechanical heart valves, and thromboembolic events. High-dose anticoagulation is recommended for antiphospholipid syndrome. Case reports of resolution of valvular vegetations after warfarin therapy in patients with antiphospholipid syndrome suggest a role for anticoagulation in the treatment of valvular disease. However, therapeutic trials are lacking.
• The efficacy of aspirin in preventing embolic phenomena with Libman-Sacks endocarditis is undetermined.
• Manage heart failure due to valvular dysfunction according to usual guidelines. Medications might include vasodilators, beta-blockers, diuretics, and digoxin.
• Patients with renal impairment and systemic lupus erythematosus are at slightly increased risk for bone marrow depression and agranulocytosis with ACE inhibitors.

Surgical Care

• Valve replacement might be required for hemodynamically significant valvular dysfunction. Mechanical prostheses are usually implanted. The use of bioprosthetic (tissue) valves is debated because of concerns regarding recurrence of disease and early prosthesis degeneration.
• Although numerous reports of uneventful valve replacement for Libman-Sacks endocarditis have been published, mortality rates in lupus patients have been reported to be as high as 25%.
• Aggressive prophylaxis and treatment of perioperative thrombotic complications are required.

Consultations

• Cardiologist for assistance with the evaluation of the nature and severity of valvular disease, management of heart failure, and evaluation for coexistent lupus cardiac pathology
• Cardiac surgeon if valve replacement is required
• Rheumatologist if underlying systemic lupus erythematosus is suggested
• Infectious disease specialist if sepsis or secondary infective endocarditis is suggested
• Neurologist for cerebrovascular complications

Diet

No special diet is required. However, patients with heart failure might need to avoid excessive sodium intake and patients receiving immunosuppression for systemic lupus erythematosus should avoid products that contain listerial organisms, such as soft cheeses.

MEDICATION

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Although no specific therapy is available for Libman-Sacks endocarditis, the following medications can be indicated for the management of valvular disease, complications, and associated conditions.

Antibiotic prophylaxis is recommended for prophylaxis of secondary infective endocarditis during procedures precipitating bacteremia. However, these guidelines are not well based on evidence in the case of Libman-Sacks valvular disease. The specific regimen depends on the nature of the valvular abnormalities, the procedure to be performed, allergies to antibiotics, and prior history of infective endocarditis. Consult guidelines, such as those provided by the American Heart Association, for specific information.

Limited trials have shown symptomatic benefit with ACE inhibitors for patients with mitral regurgitation and preserved left ventricular contractile function. A wide variety of drugs in this category can be used, including benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, and trandolapril. Avoid ACE inhibitors in patients with documented hypersensitivity and with a history of angioedema to ACE inhibitors, bilateral renal artery stenosis, severe hypotension, or second- or third-degree heart block in the absence of a pacemaker.

The hypotensive effects of ACE inhibitors can be enhanced when given concurrently with diuretics. Exercise caution in patients with hypovolemia, renal impairment, and hepatic disease. Patients with collagen vascular disease, such as systemic lupus erythematosus and scleroderma, are at slightly increased risk of bone marrow depression and agranulocytosis. Exercise caution in elderly patients; they may have decreased renal function. Hyperkalemia can result with coadministration of potassium-sparing diuretics and potassium supplements. Nonsteroidal anti-inflammatory drugs can potentiate renal dysfunction and reduce the antihypertensive effects of ACE inhibitors. Antacids can decrease the absorption of ACE inhibitors.

Drug Category: Anticoagulants

Indications for anticoagulation include atrial fibrillation, mitral stenosis, mechanical valves, thrombosis, thromboembolism, and antiphospholipid syndrome. Case reports have shown regression of valve masses with the use of anticoagulation, although data are not conclusive. For anticoagulation, warfarin is used regularly.

FOLLOW-UP

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Further Inpatient Care

Hospitalization might be required for the following related to Libman-Sacks endocarditis:

• Stabilization of heart failure
• Heparinization, if immediate anticoagulation is required (eg, thromboembolism)
• Cardiac surgery
• Treatment of infective endocarditis
• Evaluation of cerebral ischemia

Further Outpatient Care

Outpatient management issues might include the following:

• Monitoring of anticoagulation
• Adjustment of heart failure medication and monitoring of fluid status, renal function, and electrolytes
• Antibiotic prophylaxis for dental work and procedures
• Monitoring of underlying systemic lupus erythematosus disease activity with adjustments of steroids

Transfer

Cardiac surgery in patients with systemic lupus erythematosus carries a relatively higher risk of complications. Transfer to a tertiary care facility for valve replacement might be warranted in some cases.

Complications

• Complications secondary to Libman-Sacks endocarditis are uncommon.
• Valvular regurgitation and, rarely, stenosis might result in heart failure and arrhythmias, such as atrial fibrillation. See Medscape's Atrial Fibrillation Resource Center.
• Systemic emboli rarely occur as a result of valvular lesions. The risk is increased substantially in the presence of mitral stenosis, atrial fibrillation, or both.
• Secondary infective endocarditis is thought to be rare.

Prognosis

• Longitudinal data of valvular abnormalities are limited. Two series report no progression of mild or moderate regurgitation to severe regurgitation over a 2- to 3-year period and report only isolated cases of mildly progressive stenosis.
• Prognosis is probably dependent on the underlying disease activity of systemic lupus erythematosus and associated renal and myocardial dysfunction.

Patient Education

• Give patients on anticoagulation written information regarding potential drug interactions, dietary advice, the need for regular monitoring of the international normalized ratio, and warning symptoms of hemorrhage.
• Referral to an anticoagulation clinic might be appropriate.
• Educate patients about the need for antibiotic prophylaxis in case of lacerations, dental work, and other procedures.
• Information regarding systemic lupus erythematosus is available through the following Web sites:
• • Arthritis Foundation
  • Lupus Foundation of America
  • National Institutes of Health
• For excellent patient education resources, see eMedicine's patient education article Lupus (Systemic Lupus Erythematosus).

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider an underlying condition, such as systemic lupus erythematosus or antiphospholipid antibody syndrome
• Failure to consider an infective etiology of valvular vegetations
• Failure to administer antibiotic prophylaxis for procedures and dental work (in patients with known valvular abnormalities)
• Misdiagnosis as infective endocarditis, with inappropriate course of antibiotic therapy or cardiac surgery
• Failure to recognize associated pulmonary hypertension due to pulmonary pathology when evaluating the severity of valvular dysfunction

Special Concerns

Pregnancy raises several areas of concern relating to the treatment of complications of Libman-Sacks endocarditis and its associated conditions.

• Anticoagulation with warfarin during the first trimester might result in fetal abnormalities.
• Warfarin therapy during the third trimester increases the risk of hemorrhage with delivery. However, alternative anticoagulants and antiplatelet agents are not without risk and might not be as efficacious. Individualize case management.
• Maternal valvular dysfunction might decompensate, resulting in heart failure with increased risks to the mother and fetus.
• Avoid ACE inhibitors.
• Maternal systemic lupus erythematosus with anti-Ro/SS-A (Sjögren syndrome antigen A) autoantibodies is associated with fetal heart block.
• The risk of spontaneous miscarriage is increased in patients with antiphospholipid syndrome.
• Do not administer tetracycline-based antibiotics.

MULTIMEDIA

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Media file 1:  Transesophageal image of a mitral valve with masses characteristic of Libman-Sacks endocarditis.
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REFERENCES

Section 11 of 11

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12. Gleason CB, Stoddard MF, Wagner SG, et al. A comparison of cardiac valvular involvement in the primary antiphospholipid syndrome versus anticardiolipin-negative systemic lupus erythematosus. Am Heart J. Apr 1993;125(4):1123-9. [Medline].
13. Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome. Circulation. Apr 15 1996;93(8):1579-87. [Medline].
14. Khamashta MA, Cervera R, Asherson RA, et al. Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet. Jun 30 1990;335(8705):1541-4. [Medline].
15. Leung WH, Wong KL, Lau CP, et al. Association between antiphospholipid antibodies and cardiac abnormalities in patients with systemic lupus erythematosus. Am J Med. Oct 1990;89(4):411-9. [Medline].
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17. Morin AM, Boyer AS, Nataf P, Gandjbakhch I. Mitral insufficiency caused by systemic lupus erythematosus requiring valve replacement: three case reports and a review of the literature. Thorac Cardiovasc Surg. Dec 1996;44(6):313-6. [Medline].
18. Nihoyannopoulos P, Gomez PM, Joshi J, et al. Cardiac abnormalities in systemic lupus erythematosus. Association with raised anticardiolipin antibodies. Circulation. Aug 1990;82(2):369-75. [Medline].
19. O'Neill D, Magaldi J, Dobkins D, Greco T. Dissolution of intracardiac mass lesions in the primary antiphospholipid antibody syndrome. Arch Intern Med. Feb 13 1995;155(3):325-7. [Medline].
20. Roldan CA. Valvular disease associated with systemic illness. Cardiol Clin. Aug 1998;16(3):531-50. [Medline].
21. Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med. Nov 7 1996;335(19):1424-30. [Medline].
22. Roldan CA, Shively BK, Lau CC, et al. Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies. J Am Coll Cardiol. Nov 1 1992;20(5):1127-34. [Medline].
23. Skyrme-Jones RA, Wardrop CA, Wiles CM, Fraser AG. Transesophageal echocardiographic demonstration of resolution of mitral vegetations after warfarin in a patient with the primary antiphospholipid syndrome. J Am Soc Echocardiogr. May-Jun 1995;8(3):251-6. [Medline].
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Article Last Updated: Sep 16, 2008