Valvular Involvement in SLE

1. Valvular Involvement in SLE Christopher G. Stephenson, MD, FACC The Sanger Clinic, PA

2. Acknowlegements • Sreekanth Reddy, MD • Hematology/Oncology • Atlanta Cancer Care • Douglas Murphy, MD • Cardiothoracic surgeon • Peachtree Cardiovascular & Thoracic Surgeons, PA

3. Case Presentation—Initial admission (11/18/2004) of C.P. toNorthside Hospital Forsyth (Cummings, GA) • 26 y/o m with pmhx of SLE , aPL (+ IgG, IgM; + LAC), idiopathiccardiomyopathy (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

4. 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

5. 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; UA300mg/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

6. 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.

7. 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

8. 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

9. Problem List • Splenic infarct • Multiple, bilateral cerebral hemispheric infarcts, likely embolic in origin • MV vegetation of indeterminate etiology (persistently culture-negative including fastidious pathogens) with associated severe MR • Severe thrombocytopenia, resistant to high dose steroids, IVIg, platelet transfusions • Anemia with evidence of hemolysis (Elevated LDH—1160, + schistocytes) • SLE/immunocompromised state • aPL Ab + LAC—possible hypercoaguable state/APS • ARF; proteinuria, and hematuria • Inferior wall hypokinesis/mild LV systolic dysfuction—cardiaccath not performed

10. Questions? • Can we apply William of Occam’s principle of parsimony to this case? • Is there a unifying diagnosis? • How do we proceed? • Resurrect Sir William Osler, then consult him. • Transfer the patient to CMC/Carolinas Heart Institute for further evaluation and management. • When in doubt, choose C • Any thoughts/suggestions?

11. Choice C—Call a CT surgeon Photos courtesy of Douglas A. Murphy, MD

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

13. Posterior MV leaflet with multiple friable vegetations along leaflet edge

14. 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

15. 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!

16. 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.

17. 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.

18. Study Results

19. 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.

20. 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

21. Verrucous endocarditis • Libman-Sacks (verrucous) endocarditis is a not uncommon complication of SLE • Higher frequency (43 percent) has been noted when more sensitivetransesophageal echocardiography is performed

22. 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.

23. 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

24. 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

25. 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.

27. 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

28. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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 Criteria for Antiphospholipid Syndrome APS is present if at least 1 clinical and 1 lab criteria are met. Adapted from Sapporo Conference, 1999

37. 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

38. 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

39. 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

40. 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.

41. 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.

42. 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.