Transcript Document

Valvular Involvement in
SLE
Christopher G. Stephenson, MD, FACC
The 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:


Social hx:



None
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; 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
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), nonmobile 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 List
1)
2)
3)
4)
5)
6)
7)
8)
9)
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—
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?
c)
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
o
Any thoughts/suggestions?
a)
b)
Choice C—Call a CT surgeon
Photos 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 Results
Echo 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


Valvular thrombotic lesions that produce significant
emboli (cerebral, visceral, coronary)


Response to trauma, local turbulence, circulating immune
complexes, vasculitis, and hypercoagulable states
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
APS is present if at least 1 clinical and 1 lab criteria are met.


Clinical criteria



Vascular thrombosis
Pregnancy morbidity



Lab criteria
Unexplained fetal
death beyond 10wks
Premature birth before
34wks
3 or more unexplained
spontaneous abortions
before 10wks

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, 1999
Cardiac manifestations of aPL
Syndrome

Valvular disease





Coronary artery disease





Vegetations
Leaflet thickening
Regurgitation>>>>stenosis
Mitral>aortic>pulmonic>tricuspid involvement
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, evidencebased therapies and assist in preventing
some of the its adverse sequelae.
