the heart of the matter

clinical problem-solving

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with

the reader (regular type). The authors’ commentary follows.

n engl j med 368;10 nejm.org march 7, 2013944

From the Division of Immunology and Rheumatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA (L.T.); and the Divisions of Rheu-matology (J.Y.) and Cardiology (B.M., C.B.) and the Department of Medicine (G.D.), University of California, San Fran-cisco; San Francisco General Hospital (C.B.); and the San Francisco Veterans Affairs Medical Center (G.D.) — all in San Francisco. Address reprint requests to Dr. Tarter at the Division of Immunol-ogy and Rheumatology, Department of Medicine, Stanford University Medical Center, 1000 Welch Rd., Suite 203, Palo Alto, CA 94304, or at [email protected].

N Engl J Med 2013;368:944-50.DOI: 10.1056/NEJMcps1114207Copyright © 2013 Massachusetts Medical Society.

A 22-year-old woman presented to the emergency department with a 4-week history of cough, progressive shortness of breath, subjective fevers, and malaise. On the day of admission, she was unable to walk farther than one city block without stopping to rest. She also noted new swelling in both legs.

This patient’s progressive dyspnea may be due to volume overload, primary pulmo-nary processes, or anemia. The combination of dyspnea and lower-extremity edema suggests volume overload, typically explained by cardiac, hepatic, or renal failure. The duration of the reported problems and the association with systemic symptoms suggest an inflammatory, infectious, or malignant cause.

The patient reported having arthralgias in her hands and knees that had begun 3 months before admission and were worse in the morning. Her medical history in-cluded migraine headaches since she was 10 years of age and subclinical herpes sim-plex virus type 2 infection. Three years earlier, she had undergone an uncomplicated delivery of a healthy baby at 40 weeks’ gestation; she reported no other pregnancies. She was taking no prescription medications. Originally from El Salvador, she had im-migrated to the United States 5 years earlier but had not traveled recently. She worked in food services. She did not smoke cigarettes or use illicit drugs and rarely consumed alcohol. A sister in El Salvador had received a diagnosis of kidney disease of uncertain cause. The patient did not have patchy alopecia, aphthous ulcerations, dry eyes, dry mouth, rashes, or Raynaud’s phenomenon.

Rheumatoid arthritis could explain subacute symmetric arthralgias in a young woman, but severe pulmonary or cardiac manifestations early in the disease course would be unusual. Systemic lupus erythematosus (SLE) with renal involvement could account for the arthralgias and volume overload. Sarcoidosis can cause ar-thralgias with pulmonary or cardiac involvement. Patients with dermatomyositis or polymyositis may present with early interstitial lung disease and concomitant ar-thritis. Subacute bacterial endocarditis could also explain this constellation of symptoms. The patient’s Central American origin raises the possibility of Chagas’ cardiomyopathy. Other infectious causes to consider include tuberculosis and infec-tion with endemic fungi, such as histoplasmosis or paracoccidioidomycosis. The history of kidney disease in her sister raises the question of hereditary renal condi-tions, such as Alport’s disease or polycystic kidney disease, although they do not cause arthralgias; there could also be a shared predisposition to multisystem disease that affects the kidney (e.g., SLE). Thyroid disease (hyperfunction or hypofunction) should also be considered as a cause of at least some of her presenting symptoms.

The Heart of the MatterLaura Tarter, M.D., Jinoos Yazdany, M.D., M.P.H., Brian Moyers, M.D.,

Christopher Barnett, M.D., and Gurpreet Dhaliwal, M.D.

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF ILLINOIS on March 9, 2013. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.


n engl j med 368;10 nejm.org march 7, 2013 945

The patient was a well-nourished woman who appeared anxious, with mildly increased respira-tory effort. Her temperature was 36.9°C, blood pressure 115/77 mm Hg, resting heart rate 114 beats per minute, and respiratory rate 18 breaths per minute. Oxygen saturation was 100% while she was breathing ambient air. She had tachycar-dia with a regular rhythm, a loud first heart sound, and a normal second heart sound. A grade 2/6 systolic murmur was best heard at the base, and a low-pitched grade 2/4 rumbling diastolic murmur was best heard at the apex. The jugular venous pressure was 12 cm of water. Faint bibasi-lar rales and trace bipedal pitting edema were noted. She did not have hepatosplenomegaly. Subtle synovitis was present in four metacarpo-phalangeal joints and in her left wrist, and she had three, bilaterally distributed subungual splinter hemorrhages.

Congestive heart failure can develop in a young patient owing to undiagnosed congenital heart disease, accelerated coronary disease, nonischemic cardiomyopathy, toxins, viral myocarditis, or val-vulopathies. The systolic murmur may reflect a primary valvular disorder such as a bicuspid aor-tic valve or residual sclerosis or stenosis from antecedent rheumatic fever, but it may represent a flow murmur in a patient with tachycardia and volume overload. The diastolic murmur strongly suggests mitral stenosis, which is most com-monly caused by rheumatic heart disease. The presence of congestive heart failure, murmurs, polyarticular synovitis, and splinter hemorrhages is highly suggestive of endocarditis, which may in turn have an infectious, inflammatory, or thrombotic cause. The absence of fever on pre-sentation is not particularly informative, but the absence of fever on continued monitoring, if sus-tained, would increase suspicion that her illness has a noninfectious cause. Patients with atrial myxoma may also present with murmurs, em-bolic phenomena, and systemic manifestations. Splinter hemorrhages are classically associated with subacute bacterial endocarditis but can be seen in association with other embolic condi-tions, such as the antiphospholipid syndrome and the hypereosinophilic syndrome, as well as with nail trauma. SLE can cause myocarditis, al-though pericarditis and Libman–Sacks endocar-ditis are more common cardiac manifestations.

The white-cell count was 8200 per cubic millime-ter, with 85% neutrophils, 10% lymphocytes, and 5% monocytes. The hemoglobin level was 9.7 g per deciliter, and the hematocrit was 29.3%, with a mean corpuscular volume of 81 μm3. The platelet count was 333,000 per cubic millimeter. A periph-eral-blood smear did not show spherocytes or schistocytes. The erythrocyte sedimentation rate was 30 mm per hour. The C-reactive protein level was 3.0 mg per deciliter (normal value, <10.0). The serum urea nitrogen level was 22 mg per deciliter (7.9 mmol per liter), and the serum creatinine level was 1.8 mg per deciliter (159 μmol per liter). Results of serum electrolyte and coagulation stud-ies showed no abnormalities. The results of liver-function tests were normal except for a serum albumin level of 2.2 g per deciliter. Urinalysis showed 3+ protein and 2 to 5 red cells per high-power field.

Lymphopenia may occur in patients with SLE, human immunodeficiency virus (HIV) infection, Hodgkin’s disease, or a state of glucocorticoid excess, although none of the findings on physi-cal examination of this patient suggest the last. She also has a borderline microcytic-to-normo-cytic anemia, which could indicate iron deficien-cy or may reflect anemia of chronic disease. The absence of eosinophils on the peripheral-blood smear is inconsistent with the hypereosinophilic syndrome. Impaired renal function associated with an active urine sediment suggests glomeru-lar disease. The combination of high-grade pro-teinuria, hypoalbuminemia, and edema is char-acteristic of the nephrotic syndrome, which can be caused by minimal-change disease, focal seg-mental glomerulosclerosis, or membranous ne-phropathy, and is associated with many of the aforementioned conditions, including SLE, can-cer, and HIV infection. At this point, SLE with Libman–Sacks endocarditis would be a plausible unifying diagnosis.

Four blood cultures were sterile, and the patient remained afebrile throughout her hospital stay. The anti–streptolysin O antibody titer was within normal limits. Testing was negative for antibodies to HIV and to coccidioidomycosis, and a viral-load test for HIV was negative. The antinuclear antibody titer was greater than 1:640, with a dif-fuse pattern. Antibodies to double-stranded DNA





(dsDNA) were present at a titer of 1:640. A test for antibodies to nuclear ribonucleoprotein was posi-tive, at 58 U per milliliter. Anti-Ro (SS-A) and anti-La (SS-B) antibodies, anti-Smith antibodies, and antineutrophil cytoplasmic antibodies (ANCA) were not detected. The C3 level was 80 mg per deciliter (normal range, 86 to 184), and the C4 level was normal. Anticardiolipin antibodies of

the IgG type were present at a level of 24 GPL units per milliliter (normal value, <20); IgM-type anti-cardiolipin antibodies were within normal limits, as were IgG-type and IgM-type β2 glycoprotein 1 antibodies. Testing for lupus anticoagulant was negative. Urine sediment showed red-cell casts. A 24-hour urine collection revealed 7.6 g of protein. A chest radiograph showed pulmonary edema. Axial computed tomography (CT) of the chest, ab-domen, and pelvis without the administration of contrast material showed no masses or lymphade-nopathy.

High titers of anti-dsDNA antibodies are specific for SLE. The 1997 update of the 1982 American Col-lege of Rheumatology revised criteria for classifi-cation of SLE is fulfilled by the following find-ings: a positive test for antinuclear antibodies, immunologic findings (dsDNA), hematologic in-volvement (lymphopenia), arthritis, and evidence of glomerular injury (proteinuria [>0.5 g of pro-tein per day] and red-cell casts). Serologic studies and clinical features relevant to other glomerulo-nephritides (anti–streptolysin O, ANCA, and HIV) are negative. The CT results (albeit of limited value without the administration of contrast ma-terial) make lymphoma unlikely.

Review of the patient’s medical record revealed that a rapid plasma reagin test, performed 3 years before admission as part of a standard prenatal panel, was positive at a titer of 1:4. Two Treponema pallidum particle agglutination assays and an anti-nuclear antibody test were negative at that time. Post partum, the hematocrit was 38.1%, and the serum creatinine level was 0.48 mg per deciliter (42.4 μmol per liter).

The low titer on the rapid plasma reagin test and the repeatedly negative results on T. pallidum par-ticle agglutination assays suggest a false positive

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Figure 1. Findings on Transthoracic Echocardiography at the Time of Presentation.

The parasternal long-axis view in Panel A shows a com-plex mass of soft tissue infiltrating the posterior wall of the left ventricle and encasing the posterior mitral-valve leaflet (arrow). The apical four-chamber view in Panel B shows encasement of the posterior mitral-valve leaflet by the soft-tissue mass (arrow) and involvement of the anterior mitral-valve leaflet. The mean diastolic mitral-valve pressure gradient of 16 mm Hg, shown on con-tinuous-wave Doppler imaging in Panel C (arrow), is consistent with severe mitral stenosis.





result, such as can be found in a number of infec-tious, autoimmune, and malignant conditions, including the antiphospholipid syndrome.

A transthoracic echocardiogram showed a large, irregular mass encasing the posterior leaflet of the mitral valve and resulting in severely reduced leaflet mobility (Fig. 1; and Video 1, available with the full text of this article at NEJM.org). There was severe leaflet thickening, with a mean diastolic transmitral gradient of 16 mm Hg. The pulmo-nary-artery systolic pressure was 67 mm Hg. The mass extended into the basal posterior and inferi-or walls of the left ventricle and the posterior wall of the left atrium. Left ventricular function and right ventricular function were normal. Transesophageal echocardiography (Video 2) and cardiac magnetic resonance imaging (Fig. 2) con-firmed these findings and showed involvement of the anterior leaflet and chordae tendineae, along with extensive spread into the atrioventricular groove.

This large, infiltrative mass may be causing heart failure due to valvular involvement, hemodynam-ic obstruction, or both. In addition, it is probably the source of the embolic phenomena (e.g., splin-ter hemorrhages). The encasement of the mitral valve is causing severe mitral stenosis and ac-counts for both the apical diastolic murmur and the dyspnea on exertion.

The most common intracardiac tumor is atrial myxoma, which frequently causes emboli and striking immunologic phenomena. Howev-er, myxomas are typically pedunculated and mobile. In this case, the degree of invasiveness and adherence is more characteristic of a pri-mary cardiac tumor, such as rhabdomyosarcoma or angiomyosarcoma, or a metastasis. The pa-tient’s presentation is otherwise suggestive of SLE, but the large size of the mass is not typical for Libman–Sacks endocarditis. It is plausible that her employment in food services may put her at risk for a culture-negative endocarditis (e.g., brucellosis or Q fever), but signs of infec-tion, such as fever, are absent. Although bland thrombus due to the antiphospholipid syndrome or the nephrotic syndrome is a consideration, invasiveness and valvular encasement are not characteristic of thrombus.

A specimen from a renal biopsy revealed changes characteristic of diffuse proliferative lupus ne-

phritis (class IV) and membranous lupus nephritis (class V), with moderate activity and moderate chronicity. There were no platelet-fibrin thrombi (Fig. 3).

These histologic results confirm the diagnosis of SLE. It is conceivable that emboli from a myxoma (or some other tumor) could mediate histologic changes similar to those seen in SLE nephritis. However, SLE with an extremely invasive form of Libman–Sacks endocarditis is a more likely diag-nosis.

With histopathological evidence of lupus nephri-tis, a presumptive diagnosis of Libman–Sacks en-docarditis was made. Cardiac biopsy was deferred, owing to the high risk associated with the proce-dure. The cardiac surgery service determined that the extent of abnormal tissue surrounding the mi-tral valve, with encasement of the left circumflex coronary artery, made surgical management of mitral stenosis with resection of the mass impos-sible. The patient was treated with glucocorti-coids, mycophenolate mofetil, an angiotensin-converting–enzyme inhibitor, diuretics, and warfarin. Her lower-extremity edema and exer-tional dyspnea improved markedly over the next several months. Repeat transthoracic echocar-diography 11 months after her initial presentation revealed a reduction in the size of the mass and a decrease in the mean diastolic mitral gradient to 6.9 mm Hg (Fig. 4, and Video 3). The serum creati-nine, albumin, and C3 levels had normalized, the dsDNA antibody titer decreased to 1:40, and the

Videos showing echocardiograms are available at NEJM.org

Figure 2. Findings on Magnetic Resonance Imaging at Presentation.

A transverse cardiac image obtained without the ad-ministration of gadolinium shows a mass extending into the left atrium and left ventricle (arrow).





urinary protein excretion was less than 500 mg in 24 hours. Two years after the diagnosis, the patient’s laboratory results and symptoms remained stable.

After immunosuppressive therapy for SLE, the cardiac mass decreased in size, and there was a commensurate hemodynamic improvement in the

mitral stenosis. Characteristics of the mass on cardiac imaging, combined with the serologic and pathological evidence of active SLE, provide strong support for the diagnosis of Libman–Sacks endocarditis.

Commen ta r y

Although SLE was a leading consideration at multiple points in this case, the clinicians and the discussant were repeatedly forced to consider whether additional data supported a diagnosis of SLE and SLE-related phenomena or provided con-tradictory information that could change the working diagnosis. This cognitive process in-volved both pattern recognition and analytic rea-soning. For instance, symmetric arthralgias of new onset are characteristic of early SLE, but co-incident severe congestive heart failure is highly atypical. The discovery of murmurs and splinter hemorrhages suggested endocarditis, but the pa-tient did not have other signs of infection.

A principal challenge was to distinguish Lib-man–Sacks endocarditis from other causes of a cardiac mass. The most common primary car-diac tumors are myxomas, which are typically pedunculated and do not invade the ventricular myocardium.1 Rhabdomyomas can be invasive and may regress spontaneously, but they classi-cally occur in young children with tuberous sclerosis. Cardiac fibromas, lipomas, and sarco-mas, as well as metastatic disease, can have characteristics on imaging that are similar to those of the mass seen in our patient, but such lesions would not be expected to improve with-out surgical intervention or systemic chemothera-py. Endocardial thrombosis was also a consider-ation, but multiple cardiac imaging techniques revealed invasion of the ventricular myocardi-

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Figure 3. Glomerular Features in the Renal-Biopsy Specimen.

The photomicrograph in Panel A shows endocapillary proliferation with large subendothelial deposits (yellow arrow) and subepithelial deposits (blue arrow) (methe-namine silver and periodic acid–Schiff stains). The photomicrograph in Panel B shows mesangial (yellow arrow) and capillary-loop (blue arrow) immunofluores-cence staining (present for IgG, IgM, IgA, C3, and C1q). The electron micrograph in Panel C confirms the pres-ence of numerous irregular mesangial, subendothelial (blue arrow), and subepithelial deposits (yellow arrow).





um, which would not be consistent with this diagnosis.

In 1924, Emanuel Libman and Benjamin Sacks described four cases of noninfective “pe-culiar valvular and mural lesions,” which they labeled “atypical verrucous endocarditis.”2 These sterile valvular vegetations, subsequently termed Libman–Sacks endocarditis, have been reported in 13 to 65% of cases of premature death attrib-utable to SLE at autopsy.3 In more recent cohort studies involving unselected patients with SLE, valvular vegetations were reported in 7 to 11% of patients on transthoracic echocardiography4,5

and in 43% of patients on transesophageal echo-cardiography.6 Left-sided valves are most com-monly involved, and the mitral valve is more frequently affected than the aortic valve.4 On pathological evaluation, vegetations are fibrotic or consist of proliferating endothelial cells, myo-cytes, and mononuclear-cell infiltrates.7

Most Libman–Sacks vegetations are small and hemodynamically insignificant.6 However, severe valvular regurgitation and symptoms of heart failure develop in approximately 10% of patients with SLE who have valvular lesions,5,6,8 and cases of massive mitral-valve vegetations, as noted in the present case, have been reported.9,10 Case reports have described localization to the poste-rior leaflet of the mitral valve and involvement of the ventricular mural endocardium, chordae, and papillary muscles.2,11

A high level of disease activity and the pres-ence of lupus nephritis have been identified as risk factors for Libman–Sacks lesions.4 A recent meta-analysis also showed that the risk of non-infective valvular vegetations was increased by a factor of 3 among patients with SLE who had antiphospholipid antibodies, as compared with

patients who did not have these antibodies.12

Our patient had multiple risk factors, including highly active disease, severe lupus nephritis, and a positive (albeit low-titer) anticardiolipin anti-body test.

The optimal treatment for Libman–Sacks endo-carditis is unknown. A decline in the prevalence

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Figure 4. Findings on Transthoracic Echocardiography 11 Months after Presentation.

The parasternal long-axis view in Panel A shows a marked reduction in the prominence of the previously noted soft-tissue mass infiltrating the posterior wall of the ventricle and encasing the posterior mitral-valve leaflet (arrow). The apical four-chamber view in Panel B shows a marked reduction in the extent of the infil-trating soft-tissue mass (arrow) and decreased thicken-ing of both the posterior and the anterior mitral-valve leaflets. The mean diastolic mitral-valve pressure gra-dient of 6.9 mm Hg, shown on continuous-wave Dop-pler imaging in Panel C (arrow), is considerably lower than the initial value (16 mm Hg).





of the disorder at autopsy and an increase in the frequency of pathological evidence of healed le-sions since the advent of glucocorticoid therapy have led some authors to hypothesize that medical treatment is beneficial.9,13 However, several longi-tudinal cohort studies have shown no relationship between immunosuppressive medications, includ-ing cytotoxic agents, and changes in valvular le-sions,5,6,8 and the possible worsening of lesions with glucocorticoid therapy has been reported.14 Data from clinical trials assessing the effects of various treatment strategies in patients with Lib-man–Sacks endocarditis are lacking. Case reports have described surgery for SLE-related valvulop-athy, but this approach is associated with a high risk of complications.15

In this case, the clinical presentation and find-ings on renal biopsy provided strong evidence for a diagnosis of SLE. Although immunosuppressive therapy has not been shown to be an effective treatment for typical Libman–Sacks endocarditis, the reduction in the size of the cardiac lesion and long-term clinical improvement with immunosup-pression argued against a diagnosis of cardiac tu-mor and allowed the clinicians to conclude that Libman–Sacks endocarditis was the heart of the matter.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Dr. Jean L. Olson for the photographs of the renal pathological specimens, Dr. Ramin Farzaneh-Far for assistance with echocardiographic images, and Dr. Nicole Richman.

References

1. Burke A, Virmani R. More on cardiac myxomas. N Engl J Med 1996;335:1462-3.2. Libman E, Sacks B. A hitherto unde-scribed form of valvular and mural endo-carditis. Arch Intern Med 1924;33:701-37.3. Mandell BF. Cardiovascular involve-ment in systemic lupus erythematosus. Semin Arthritis Rheum 1987;17:126-41.4. Moyssakis I, Tektonidou MG, Vasil-liou VA, Samarkos M, Votteas V, Moutso-poulos HM. Libman-Sacks endocarditis in systemic lupus erythematosus: preva-lence, associations, and evolution. Am J Med 2007;120:636-42.5. Perez-Villa F, Font J, Azqueta M, et al. Severe valvular regurgitation and anti-phospholipid antibodies in systemic lupus erythematosus: a prospective, long-term, followup study. Arthritis Rheum 2005;53: 460-7.6. Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lu-pus erythematosus. N Engl J Med 1996; 335:1424-30.

7. Eiken PW, Edwards WD, Tazelaar HD, McBane RD, Zehr KJ. Surgical pathology of nonbacterial thrombotic endocarditis in 30 patients, 1985-2000. Mayo Clin Proc 2001;76:1204-12.8. Khamashta MA, Cervera R, Asherson RA, et al. Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet 1990;335:1541-4.9. Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: a study of 36 necropsy patients. Am J Med 1975;58:243-64.10. Vaughton KC, Walker DR, Sturridge MF. Mitral valve replacement for mitral stenosis caused by Libman-Sacks endo-carditis. Br Heart J 1979;41:730-3.11. Gross L. The cardiac lesions in Libman-Sacks disease: with a consideration of its relationship to acute diffuse lupus erythe-matosus. Am J Pathol 1940;16:375-408.12. Zuily S, Regnault V, Selton-Suty C, et al. Increased risk for heart valve disease

associated with antiphospholipid anti-bodies in patients with systemic lupus erythematosus: meta-analysis of echocar-diographic studies. Circulation 2011;124: 215-24.13. Tincani A, Rebaioli CB, Taglietti M, Shoenfeld Y. Heart involvement in systemic lupus erythematosus, anti-phospholipid syndrome and neonatal lupus. Rheuma-tology (Oxford) 2006;45:Suppl 4:iv8-iv13.14. Dajee H, Hurley EJ, Szarnicki RJ. Car-diac valve replacement in systemic lupus erythematosus: a review. J Thorac Cardio-vasc Surg 1983;85:718-26.15. Straaton KV, Chatham WW, Reveille JD, Koopman WJ, Smith SH. Clinically significant valvular heart disease in sys-temic lupus erythematosus. Am J Med 1988;85:645-50.Copyright © 2013 Massachusetts Medical Society.

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