Valvular Involvement in SLE

Christopher G. Stephenson, MD, FACCThe Sanger Clinic, PA

Acknowlegements

Sreekanth Reddy, MD Hematology/Oncology Atlanta Cancer Care

Douglas Murphy, MD Cardiothoracic surgeon Peachtree Cardiovascular & Thoracic Surgeons, PA

Case Presentation—Initial admission

(11/18/2004) of C.P. to Northside Hospital Forsyth (Cummings, GA) 26 y/o m with pmhx of SLE , aPL (+ IgG, IgM; + LAC),

idiopathic cardiomyopathy (reportedly resolved), thrombocytopenia (~100K) in USOGH working as 6th grade math teacher p/w LUQ pain “stabbing” in nature for several days, low grade fever (Tmax 101F)

PShx: None

Social hx: No tobacco, EtOH, or injection drug use Heterosexual, not sexually active

Meds: CellCept 1gr BID Plaquenil 200mg QD Coreg 25mg BID Altace Prednisone 5mg QD

Initial evaluation revealed: Severe thrombocytopenia (20K) CT abdomen (IV contrast)—splenic infarct Multiple sets of blood cultures drawn prior to

administration of empiric antibiotics---Negative

Initial impression: aPL-associated thrombocytopenia and thrombosis

Treatment: ASA High dose Prednisone Lovenox/Coumadin not administered due to

thrombocytopenia

Readmission 11/24/2004 (2 days after discharge) with eventual transfer to St. Joseph’s Hospital of Atlanta, GA

Presented with protracted nausea, emesis, epigastric pain, low grade fever, stable vitals. Severe thrombocytopenia (11K) WBC 7.7; Hct 32; UA300mg/dl protein, 50-100RBCs;

Creatinine 2.8 (etiology never ascertained—eventually normalized)

Blood cultures from 11/19 and 11/23—No growth CXR-unremarkable ECG—NSR, LAE, Nl axis, Nl intervals, No ST/T changes No SOB, CP, or neurological symptoms PhysEx: Pectus Excavatum, II/VI HSM @apex—L axilla;

No S3; No rub/click; abdomen benign, No stigmata of SBE, No petechiae

Right inferior quadrantanopia

Echocardiogram--TTE View Study

Note: TEE was subsequently performed which, by virtue of its poor quality and limited Doppler data added no incremental information to the TTE.

TTE findings Mild LA (43mm), LV (59mm) enlargement Inferior wall hypokinesis (TEE

corroborated this finding) LVEF~45% Valvular “vegetation” (~0.5cm), non-

mobile affixed to anterior leaflet of MV. No evidence of prolapse.

Probable severe MR by color Doppler, although limited data to assess severity of MR; jet directed centrally

MRI brain/MRA intracranial arteries

Show images

Multiple, small diffusion abnormalities in the cerebral hemispheres evident in the frontal, parietal and occipital lobes bilaterally. Multiple small “embolic” bland infarctions Normal MRA of the intracranial circulation

Problem List1) Splenic infarct2) Multiple, bilateral cerebral hemispheric infarcts, likely

embolic in origin3) MV vegetation of indeterminate etiology (persistently

culture-negative including fastidious pathogens) with associated severe MR

4) Severe thrombocytopenia, resistant to high dose steroids, IVIg, platelet transfusions

5) Anemia with evidence of hemolysis (Elevated LDH—1160, + schistocytes)

6) SLE/immunocompromised state7) aPL Ab + LAC—possible hypercoaguable state/APS8) ARF; proteinuria, and hematuria9) Inferior wall hypokinesis/mild LV systolic dysfuction—

cardiac cath not performed

Questions? Can we apply William of Occam’s principle of

parsimony to this case?

Is there a unifying diagnosis?

How do we proceed?a) Resurrect Sir William Osler, then consult him.b) Transfer the patient to CMC/Carolinas Heart Institute for

further evaluation and management.c) When in doubt, choose C

o Any thoughts/suggestions?

Choice C—Call a CT surgeonPhotos courtesy of Douglas A. Murphy, MD

Anterior leaflet of MV, with destruction of the edge of A2 causing central MR. Large nodule to right of A2 with multiple friable vegetations—Leaflet and chordae excised (not amenable to repair) and replaced with #33 ATS valve

Posterior MV leaflet with multiple friable vegetations along leaflet edge

Pathology report Largest excrescence on submitted MV tissue

measured 10x6mm. Large verrucous fibrin deposit with scattered

inflammatory cells. Striking fibrinoid necrosis at the base and within the

valve. Nodular areas of fibrosis and dystrophic calcification. Special stains for AFB, fungi and bacteria-negative

Diagnosis: Nonbacterial verrucous valvulitis of Libman-Sacks

Patient 3 weeks Post-op Laboratory Data

1/03/05 Hct=39 Platelets=333 Creatinine=1.3 PT=33.6

Patient returned to work as 6th grade math teacher!

Valvular disease in SLE Leaflet thickening tends to be diffuse; it usually

involved the mitral and aortic valves and is associated with valve regurgitation (~75%) or valve masses (50%).

Lupus valve disease is frequent (75%) regardless of the presence or absence of antiphospholipid antibodies. Antiphospholipid antibodies may not be a

primary pathogenetic factor.

An echocardiographic study of valvular heart disease associated with systemic

lupus erythematosus TEE and rheumatologic evaluations in 69 patients

with SLE Echocardiographic findings were compared with

those in 56 healthy volunteers 84 % had second evaluations a mean period of

29 months later Patients and controls were followed for 57 months

Roldan CA, et al. N Engl J Med 1996 Nov 7;335(19):1424-30.

Study ResultsEcho Findings Initial Echo (%) Follow-up Echo (%)

Valvular thickening

51 52

Valvular regurgitation

25 28

Valvular stenosis

4 3

SLE echocardiographic study--Conclusions Neither the presence of nor changes in valvular disease

were temporally related to disease activity, therapy, or the duration of SLE.

Appreciable incidence of serious complications in the patients with valvular disease. After a mean follow-up of almost five years, the combined

incidence of stroke, peripheral embolism, heart failure, infective endocarditis, and death was 22% (with valve disease) vs 15% (without valvular disease).

The incidence of stroke in patients with valvular disease was 13 percent.

Valvular disease in SLE—Clinical course 5 year follow-up—20% risk of valve related

complications: Symptomatic severe MR Infective endocarditis Ischemic stroke

Mortality 20% at 5yrs. Due to refractory heart failure, IE, CVA,

complicated post-op course

Verrucous endocarditis Libman-Sacks (verrucous) endocarditis is a

not uncommon complication of SLE Higher frequency (43 percent) has been

noted when more sensitive transesophageal echocardiography is performed

Verrucae Most commonly involve the mitral valve

(any valve can be involved)

Most commonly found in the valve recess between the ventricular wall and the posterior leaflet

Can involve the surface of the valves, valve ring, commissures.

Pathogenesis of Libman-Sacks endocarditis—proposed mechanisms Fibrin and platelet thrombi on the impaired

valves-- organization leads to fibrosis, distortion, and subsequent valvular dysfunction

Immunologic injury--initial insult to the valvular apparatus, triggering the sequence of pathogenetic events.

Deposits of immunoglobulins and complement were shown in the subendothelial layer of the valves in patients with antiphospholipid antibodies

Verrucous endocarditis--Continued Typically asymptomatic Verrucae can fragment and produce systemic

emboli, and infective endocarditis can develop on already damaged valves

Blood cultures and echocardiography should be performed whenever fever and a new murmur are noted in a patient with SLE

Antibiotic prophylaxis for patients with SLE undergoing procedures associated with a risk of developing bacteremia (such as dental care) in view of the high frequency of valvular disease

Verrucous endocarditis- Therapy Corticosteroid and/or cytotoxic therapy have

no effect upon valvular lesions steroids may facilitate healing of valvular

vegetations, which may result in marked scarring and deformity of the valve, thereby most likely leading to valve dysfunction

Anticoagulation treatment should be considered for those patients with vegetations.

Valve replacement surgery or valvuloplasty may be necessary for some patients who develop severe mitral or aortic valvular insufficiency, or, rarely for those with symptomatic stenotic lesions.

Echocardiographic appearance Usually less than 1 square centimeter

in size Irregular margins Heterogeneous echodensity Do not exhibit independent motion Most valves with masses have associated

thickening or regurgitation

The verrucae are usually near the edge of the valve and consist of accumulations of immune complexes, mononuclear cells, hematoxylin bodies, and fibrin and platelet thrombi

Differential diagnosis of a valvular mass/valve thickening Infective endocarditis

Oscillating mass independent of leaflet motion

Pseudoinfective endocarditis Clinical syndrome of active SLE that mimics IE,

thus presenting a diagnostic and therapeutic dilemma

Leukopenia Elevated aPL antibodies Negative or low positive CRP Repeatedly negative blood cultures

Differential diagnosis of a valvular mass/valve thickening Nonbacterial thrombotic endocarditis

Sterile platelet and fibrin thrombi on cardiac valves and adjacent endocardium

Response to trauma, local turbulence, circulating immune complexes, vasculitis, and hypercoagulable states

Valvular thrombotic lesions that produce significant emboli (cerebral, visceral, coronary)

NBTE uniformly have multiple, widely distributed, small and large strokes

Observed in patients with chronic wasting disease, DIC, autoimmune diseases, mucin-producing metastatic carcinomas, chronic infections

Differential diagnosis of a valvular mass/valve thickening Age-related valve degeneration

Annular calcification/sclerosis Myxomatous changes

Rheumatic valvular disease Leaflet thickening confined to the leaflet tips Chordal involvement—thickening, fusion,

calcification

Differential diagnosis of a valvular mass/valve thickening Lambl’s excresences

Found in 70-85% of adult heart valves; usually multiple

Usually arise from line of closure of the valves

Do not appear to be a primary source of embolism (rarely), and do not change in appearance over time

Usually do not occur on the arterial side of the semilunar valves or on the mural endocardium

Differential diagnosis of a valvular mass/valve thickening Papillary fibroelastoma

Most common primary cardiac valve tumor Has typical morphology—mass composed of papillary

fronds and a stalk that connects it to the endocardium Usually solitary and <1.0 cm in diameter Occur most frequently on the mid portion of the body of the

valve leaflet May present with neurologic symptoms (embolism from

fragments of tumor or adherent thrombus) or coronary involvement (embolism, obstruction of coronary ostium)

Surgical resection recommended even if asymptomatic

Antiphospholipid (aPL) Syndrome Characterized by recurrent venous and

arterial thrombosis as well as recurrent fetal (1st and 2nd trimester) loss and thrombocytopenia.

Must demonstrate presence of aPL antibodies: Anticardiolipin Lupus anticoagulant

Criteria for Antiphospholipid Syndrome

Clinical criteria Vascular thrombosis Pregnancy morbidity

Unexplained fetal death beyond 10wks

Premature birth before 34wks

3 or more unexplained spontaneous abortions before 10wks

Lab criteria aCL-IgG or IgM in

moderate or high titer 2x over 6 weeks

LA on 2 occasions at least 6 weeks apart

Adapted from Sapporo Conference, 1999Adapted from Sapporo Conference, 1999

APS is present if at least 1 clinical and 1 lab criteria are met.APS is present if at least 1 clinical and 1 lab criteria are met.

Cardiac manifestations of aPL Syndrome Valvular disease

Vegetations Leaflet thickening Regurgitation>>>>stenosis Mitral>aortic>pulmonic>tricuspid involvement

Coronary artery disease Native CAD Late bypass graft occlusion Restenosis

Intracardiac thrombus Myocardial dysfunction

Is the cardiac valve disease of APS inflammatory or thrombotic? Histologic studies suggest that fibrin deposits

are the major findings, not inflammation.

However, subendothelial antibody deposition and complement components initiating valve damage have been described, along with increased endothelial cell expression of α3β1 integrin.

Afek et al. Lupus. 1999;8:502-507

One case report suggested that anticoagulation caused disappearance of valve vegetations.

Skyrme-Jones A et al J Am Soc Echo. 1995; 8:251-256

5 year follow up study of Espinola-Zavaleta, et al

Highly selected population of patients with primary APS Predominant cardiac lesion was a noninfective valve

lesion. Oral anticoagulant treatment and aspirin

proved ineffective in terms of valvular lesion regression.

Myocardial infarction occurred in 9 (37.5%) patients. All had coronary angiography and coronary arteries were

normal in 6. J Rheumatol 2004;31:2402-7

Antiphospholipid syndrome (APS) related valvulopathy Four patients reported to have “dramatic

clinical and hemodynamic response” to treatment with prednisone when symptomatic measures failed Hence, pathogenisis of valvulopathy may

involve interaction of aPL with antigens on the valve surface, resulting in valvulitis

Nesher G., et al. Semin Arthritis Rheum. 1997 Aug;27(1):27-35.

Conclusions SLE is a complex disease with protean cardiac

manifestations (“pancarditis” etc) Prevalence of valvular disease in the setting of

SLE (+/- aPL) is likely underestimated as the valvular involvement is usually of minimal hemodynamic significance and clinically silent.

The simultaneous presence of SLE and aPL in the setting of valvular disease presents a diagnostic conundrum. Both entities are independently associated with valvular

disease and contribute to a greater likelihood of embolic events.

More conclusions There is substantial morbidity associated

with valvular involvement in SLE, especially with concomitant aPL.

Further basic and clinical investigation in this area is imperative to help elucidate the natural history of this disease so that we can provide more effective, evidence-based therapies and assist in preventing some of the its adverse sequelae.