valvular involvement in sle christopher g. stephenson, md, facc the sanger clinic, pa
TRANSCRIPT
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?
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
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.