Libman-Sacks endocarditis (otherwise known as verrucous, marantic, or nonbacterial thrombotic endocarditis) is the most characteristic cardiac manifestation of the autoimmune disease systemic lupus erythematosus. Libman and Sacks first published a description of the atypical, sterile, verrucous vegetations of this form of endocarditis in 1924.[1] The condition most commonly involves the mitral and aortic valves, but all 4 cardiac valves and the endocardial surfaces can be involved.[2]
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 the image below), 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.
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Transesophageal image of a mitral valve with masses characteristic of Libman-Sacks endocarditis.
Lesions similar to those described by Libman and Sacks also occur in association with primary or secondary antiphospholipid syndrome. However, the role of antiphospholipid antibodies in the pathogenesis of Libman-Sacks endocarditis is disputed. Malignancy and hypercoagulable states are also associated with the formation of verrucous endocarditis.
Lesions are usually clinically silent, without significant valvular dysfunction. When such dysfunction does occur, however, it can result in cardiac failure. Embolic phenomena and secondary infective endocarditis, although uncommon, can also complicate valvular abnormalities and can cause neurologic and systemic complications. The risk of systemic emboli is increased substantially in the presence of mitral stenosis, atrial fibrillation, or both.
Valvular regurgitation and, rarely, stenosis may result in heart failure and arrhythmias, such as atrial fibrillation.
The pathogenesis of Libman-Sacks endocarditis is unknown. However, antiphospholipid antibodies are frequently associated with valvular abnormalities. These autoimmune antibodies are directed against negatively charged phospholipids present in endothelial cell membranes.
Although immunohistologic studies suggest a pathogenetic role for antiphospholipid antibodies, a similar prevalence and severity of valvular disease have been described in lupus patients without these antibodies; their presence does not seem to be required.
Impairment of antithrombotic mechanisms
Impaired antithrombotic mechanisms present in patients with antiphospholipid syndrome, malignancy, and hypercoagulable states may play a role 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
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. However, data are circumstantial and may reflect improved longevity of patients. Firm conclusions cannot be made.
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 valvular 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 reported that Libman-Sacks endocarditis was found in 11% of patients with lupus.[3] 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 valvular lesions.
Coexistent leaflet thickening is noted in 71% of patients with valvular masses. Echocardiography detects valvular thickening in 19-52% of patients with systemic lupus erythematosus.
In older patients, who have a longer mean duration of systemic lupus erythematosus and have received 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 individuals with peripheral arterial thromboses, having been noted in up to 64% of patients. Leaflet thickening is the most frequent abnormality, having been noted in 10-24% of patients. Vegetationlike masses occur in 6-10% of patients.
Sex- and race-related demographics
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. In the United States, statistics show systemic lupus erythematosus to be more prevalent in black and Hispanic women.
Longitudinal data of valvular abnormalities are limited. Two series reported no progression of mild or moderate regurgitation to severe regurgitation over a 2- to 3-year period and reported 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.
Morbidity and mortality
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, valve 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 echocardiographic images in 25-61% of patients with lupus 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 in 4-26% of patients with lupus. The reported need for valve replacement varies from 1-8% of cases.
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.
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 neurologic events are often present, making the specific contribution of valvular abnormalities difficult to determine.
A study by Roldan et al, however, indicated that in patients with systemic lupus erythematosus, Libman-Sacks endocarditis increases the risk for embolic cerebrovascular disease. The 6-year study involved 30 patients with acute neuropsychiatric systemic lupus erythematosus (NPSLE), 46 patients with systemic lupus erythematosus but without NPSLE, and 26 healthy controls, with members of the study followed up for a median period of 52 months.[4]
The results of the study indicated that Libman-Sacks vegetations are an independent risk factor for NPSLE, neurocognitive dysfunction, and brain lesions, either separately or in a combination of all three. According to the report, the number of cerebromicroemboli per hour was three-fold greater in patients with vegetations, while cerebral blood flow was lower and the incidence of neurocognitive dysfunction, cerebral infarcts, and strokes/transient ischemic attacks and overall NPSLE events was higher. Brain lesion load was also greater.[4]
Give patients on anticoagulation written information regarding potential drug interactions, dietary advice, the need for regular monitoring of the international normalized ratio, and the warning symptoms of hemorrhage. Referral to an anticoagulation clinic may be appropriate.
Educate patients about the need for antibiotic prophylaxis in case of lacerations or in instances of dental work or 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 patient education information, see Lupus (Systemic Lupus Erythematosus).
Persons with Libman-Sacks endocarditis are usually asymptomatic. Patients who do become symptomatic, however, can display the following:
Cardiac failure - May develop secondary to valvular dysfunction (most commonly mitral regurgitation), leading to dyspnea, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, and lethargy
Cerebrovascular embolism - Can lead to symptoms of cerebral ischemia, including focal weakness and/or numbness, visual loss, dysphasia, dysarthria, dysphagia, and memory loss
Systemic thromboembolism - A rare manifestation that 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 - May 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
In addition, symptoms of systemic lupus erythematosus may be noted, including a history of rash, arthritis (joint pain and swelling), and sweating.
Antiphospholipid syndrome
Features of antiphospholipid syndrome may be noted in the history, including recurrent miscarriage, arterial thromboses, venous thromboses, and/or thrombocytopenia.
Patients may report pain, focal neurologic symptoms (eg, focal weakness and/or numbness, visual loss, dysphasia, dysarthria, dysphagia, memory loss), numbness and discoloration of the extremities, and ischemic chest pain with arterial thromboses.
Venous thromboembolism may result in peripheral swelling, pleuritic chest pain, dyspnea, and hemoptysis. Neurologic symptoms due to cerebral ischemia can also occur in the event of a paradoxical embolus.
Physical examination findings can be normal. In symptomatic cases, however, the following cardiac murmurs may be heard:
Ejection systolic murmur (crescendo decrescendo) - This is most commonly the result of a hyperdynamic state caused by 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) may occur, but only rarely is this due to Libman-Sacks endocarditis.
The following signs of ventricular enlargement and cardiac failure may be noted in Libman-Sacks endocarditis:
Lab studies to test for Libman-Sacks endocarditis should include the following:
Blood cultures - Infective endocarditis should be excluded
Complete blood count (CBC) - Neutrophilia may indicate infection; coexistent anemia may be present
Antiphospholipid antibody - Including anticardiolipin antibody, lupus anticoagulant, Venereal Disease Research Laboratory (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-deoxyribonucleic acid (DNA) antibody assay (double stranded) - A workup for systemic lupus erythematosus may be indicated
Chest radiography
Cardiomegaly and pulmonary congestion may be noted on chest radiography; calcified masses and valvular tissue are possible but rare.
Echocardiography
Transthoracic echocardiography (TTE) is valuable for the initial evaluation of cardiac murmurs and for quantification of left atrial volume and left ventricular volume, mass, and contractile function. Transesophageal echocardiography (TEE) is useful in the detection of valvular lesions (especially in the left-sided valves), with greater sensitivity and specificity for this than TTE can achieve.
Angiography
Coronary angiography can be performed 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.
Whether transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) should be used depends on the clinical scenario.
TTE is most appropriate for the initial evaluation of cardiac murmurs and quantification of left atrial volume and left ventricular volume, mass, and contractile function.
One study compared TTE with TEE for the diagnosis of Libman-Sacks endocarditis.[6] Using TEE as the standard, TTE demonstrated low sensitivity (63% overall, 11% for valve vegetations), low specificity (58%), low negative predictive value (40%), and 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.
The use of 3-dimensional (3D) echocardiography in Libman-Sacks endocarditis has been described.[7]
Results of echocardiography
Irregular borders, heterogeneous echodensity, and an absence of 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 10mm. The basal portion and midportion 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.
TEE offers superior resolution of cardiac valves and helps to detect valvular lesions (especially in left-sided valves) with greater sensitivity and specificity than TTE.
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 computed tomography [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 for determining pulmonary artery pressure and pulmonary vascular resistance because cardiac and pulmonary pathology can occur with lupus. Use caution because the severity of valvular dysfunction in the presence of pulmonary disease may be overestimated.
The different stages of Libman-Sacks endocarditis have been described as active, active and healed, and healed lesions. These can be characterized as follows:
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.
No specific therapy is indicated for Libman-Sacks endocarditis. Manage heart failure due to valvular dysfunction according to usual guidelines.[8] Medications may include vasodilators, beta blockers, diuretics, and digoxin. The efficacy of aspirin in preventing embolic phenomena with Libman-Sacks endocarditis is undetermined.
Patients with renal impairment and systemic lupus erythematosus are at a slightly increased risk for bone marrow depression and agranulocytosis with angiotensin-converting enzyme (ACE) inhibitors.
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 may be warranted in some cases.
Diet
No special diet is required. However, patients with heart failure may 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.
Inpatient care
Hospitalization may be required for the following treatments 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
Outpatient care
Outpatient management issues may 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
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 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.
Antibiotics
Antibiotic therapy 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 strongly 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.
Warfarin
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.
Valve surgery may be required for hemodynamically significant valvular dysfunction.[9, 10] 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 in valve surgery.
Pregnancy raises several areas of concern relating to the treatment of complications of Libman-Sacks endocarditis and its associated conditions. The following considerations are important:
Anticoagulation with warfarin during the first trimester may 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 may not be as efficacious; individualize case management
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
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
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. Anticoagulation may have a role in valvular disease treatment, based on case reports that valvular vegetations resolved after warfarin therapy in patients with antiphospholipid syndrome. However, therapeutic trials are lacking.
Outpatient follow-up considerations include monitoring of patients on anticoagulation therapy. Patient referral to an anticoagulation clinic may be appropriate.
Clinical Context:
Warfarin is an oral anticoagulant that suppresses hepatic synthesis of vitamin K–dependent clotting factors. It is well absorbed orally, metabolized in the liver, and excreted in the urine and feces. Warfarin has a half-life of 0.5-1.5 day.
A loading regimen is usually used for initiation of therapy. Titrate the maintenance dose to the desired blood prothrombin time and international normalized ratio (INR); the desired INR depends on the indication for anticoagulation, the age of the patient, and the risks of bleeding versus thromboses. High-dose anticoagulation (INR 3-4) is usually indicated for antiphospholipid syndrome and mechanical valves. Warfarin is available in 1-, 2-, 2.5-, 5-, 7.5-, and 10-mg tablet sizes.
Indications for anticoagulation include atrial fibrillation, mitral stenosis, mechanical valves, thrombosis, thromboembolism, and antiphospholipid syndrome. Case reports have shown regression of valvular masses with the use of anticoagulation, although data are not conclusive. For anticoagulation, warfarin is used regularly.
Xiushui (Mike) Ren, MD, Cardiologist, The Permanente Medical Group; Associate Director of Research, Cardiovascular Diseases Fellowship, California Pacific Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Elizabeth W Ryan, MBBS, Visiting Medical Officer, Department of Medicine, Division of Cardiology, Barwon Health, Australia
Disclosure: Nothing to disclose.
Elyse Foster, MD, Professor Emeritus of Clinical Medicine, Department of Medicine, Division of Cardiology, University of California, San Francisco, School of Medicine
Disclosure: Received grant/research funds from Abbott Vascular Structural Heart for research.
Chief Editor
Richard A Lange, MD, MBA, President, Texas Tech University Health Sciences Center, Dean, Paul L Foster School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Craig T Basson, MD, PhD Gladys and Roland Harriman Professor of Medicine, Director of the Center for Molecular Cardiology, Director of Cardiovascular Research, Division of Cardiology, Department of Medicine, Weill Cornell Medical College; Attending Physician, New York Presbyterian Hospital
Craig T Basson, MD, PhD is a member of the following medical societies: American College of Cardiology and American Heart Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
References
Libman E, Sacks B. A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med. 1924. 33:701-37.
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