Valvular Involvement in SLE

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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 PresentationInitial 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

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. Josephs 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
  ascertainedeventually normalized)
• Blood cultures from 11/19 and 11/23No growth
• CXR-unremarkable
• ECGNSR, LAE, Nl axis, Nl intervals, No ST/T
  changes
• No SOB, CP, or neurological symptoms
• PhysEx Pectus Excavatum, II/VI HSM _at_apexL
  axilla No S3 No rub/click abdomen benign, No
  stigmata of SBE, No petechiae
• Right inferior quadrantanopia

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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.

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TTE findings

• Mild LA (43mm), LV (59mm) enlargement
• Inferior wall hypokinesis (TEE corroborated this
  finding)
• LVEF45
• 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

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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

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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
  LDH1160, schistocytes)
• SLE/immunocompromised state
• aPL Ab LACpossible hypercoaguable state/APS
• ARF proteinuria, and hematuria
• Inferior wall hypokinesis/mild LV systolic
  dysfuctioncardiac cath not performed

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Questions?

• Can we apply William of Occams 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?

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Choice CCall a CT surgeon Photos courtesy of
Douglas A. Murphy, MD
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Anterior leaflet of MV, with destruction of the
edge of A2 causing central MR. Large nodule to
right of A2 with multiple friable
vegetationsLeaflet and chordae excised (not
amenable to repair) and replaced with 33 ATS
valve
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Posterior MV leaflet with multiple friable
vegetations along leaflet edge
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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

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Patient 3 weeks Post-op

• Laboratory Data 1/03/05
• Hct39
• Platelets333
• Creatinine1.3
• PT33.6
• Patient returned to work as 6th grade math
  teacher!

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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.

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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 7335(19)1424-30.

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Study Results
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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.

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Valvular disease in SLEClinical course

• 5 year follow-up20 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

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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

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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.

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Pathogenesis of Libman-Sacks endocarditisproposed
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

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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

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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.

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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

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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
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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

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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

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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 involvementthickening, fusion,
  calcification

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Differential diagnosis of a valvular mass/valve
thickening

• Lambls 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

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Differential diagnosis of a valvular mass/valve
thickening

• Papillary fibroelastoma
• Most common primary cardiac valve tumor
• Has typical morphologymass composed of papillary
  fronds and a stalk that connects it to the
  endocardium
• Usually solitary and lt1.0 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

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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

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Criteria for Antiphospholipid Syndrome
APS is present if at least 1 clinical and 1 lab
criteria are met.

• Lab criteria
• aCL-IgG or IgM in moderate or high titer 2x over
  6 weeks
• LA on 2 occasions at least 6 weeks apart

• Clinical criteria
• Vascular thrombosis
• Pregnancy morbidity
• Unexplained fetal death beyond 10wks
• Premature birth before 34wks
• 3 or more unexplained spontaneous abortions
  before 10wks

Adapted from Sapporo Conference, 1999
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Cardiac manifestations of aPL Syndrome

• Valvular disease
• Vegetations
• Leaflet thickening
• Regurgitationgtgtgtgtstenosis
• Mitralgtaorticgtpulmonicgttricuspid involvement
• Coronary artery disease
• Native CAD
• Late bypass graft occlusion
• Restenosis
• Intracardiac thrombus
• Myocardial dysfunction

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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 a3ß1 integrin.
• Afek et al.
• Lupus. 19998502-507
• One case report suggested that anticoagulation
  caused disappearance of valve vegetations.
• Skyrme-Jones A et al
• J Am Soc Echo. 1995 8251-256

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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 2004312402-7

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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 Aug27(1)27-35.

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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.

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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.