Arthritis & Rheumatism (Arthritis Care & Research)

Vol. 53, No. 3, June 15, 2005, pp 460 467

DOI 10.1002/art.21162
2005, American College of Rheumatology

ORIGINAL ARTICLE

Severe Valvular Regurgitation and

Antiphospholipid Antibodies in Systemic Lupus
Erythematosus: a Prospective, Long-Term,
Followup Study
FELIX PEREZ-VILLA, JOSEP FONT, MANEL AZQUETA, GERARD ESPINOSA, CARLES PARE,
RICARD CERVERA, JOAN C. REVERTER, MIGUEL INGELMO, AND GINES SANZ

Objective. To assess whether the presence of antiphospholipid antibodies is related to the incidence and progression of
severe valvular dysfunction and the need for valve replacement in patients with systemic lupus erythematosus (SLE).
Methods. In this prospective, long-term followup study, the initial echocardiographic ndings in a cohort of 61 consecutive SLE patients were compared with those of 40 matched controls. All patients were serially evaluated for 14 3 years
and had a followup echocardiogram 8 3 years after the initial evaluation. Serial determinations of anticardiolipin
antibodies and lupus anticoagulant were performed in all cases.
Results. The number of SLE patients with valvular abnormalities increased from 39% to 73% between the initial and the
followup echocardiography, but only 7 patients (12%) developed severe valvular regurgitation. Severe valvular regurgitation was signicantly associated with the presence of high levels of IgG anticardiolipin antibodies (P 0.001). The
combined incidence of stroke, peripheral embolism, need for valve surgery, and death was 86% in patients with severe
valvular regurgitation, compared with 25% in those without (P 0.003).
Conclusion. In SLE patients, the presence of high levels of IgG anticardiolipin antibodies is associated with the
development of severe valvular regurgitation and with a high incidence of thromboembolic events and the need for
valvular surgery.
KEY WORDS. Valvular regurgitation; Antiphospholipid; Systemic lupus erythematosus.

INTRODUCTION
Valvular thickening and valve vegetations are frequent in
patients with systemic lupus erythematosus (SLE); they
usually are associated with mild valvular regurgitation
that is clinically irrelevant in a majority of patients (110).
However, about 10% of SLE patients develop severe valvular regurgitation, with symptoms of heart failure, progressive left ventricular dysfunction, and need for surgery
(1,3,10).
Dr. Fonts work was supported by a government grant
from Fondo de Investigaciones Sanitarias (FIS PI03/0280).
Felix Perez-Villa, MD, Josep Font, MD, Manel Azqueta,
MD, Gerard Espinosa, MD, Carles Pare, MD, Ricard
Cervera, MD, Joan C. Reverter, MD, Miguel Ingelmo, MD,
Gines Sanz, MD: Hospital Clinic, IDIBAPS, Barcelona,
Spain.
Address correspondence to Josep Font, MD, Department
of Systemic Autoimmune Diseases, Hospital Clinic, Villarroel, 170 Barcelona 08036, Spain. E-mail: jfont@clinic.ub.es.
Submitted for publication July 31, 2004; accepted in revised form January 3, 2005.

460

Attempts to identify patients at risk of developing severe

valvular dysfunction have been unsuccessful so far. Some
authors have found an association between valvular abnormalities detected by transthoracic echocardiography and
the presence of antiphospholipid antibodies (aPL) (2 4,7,8).
However, other authors (5,6,9), some using a more sensitive diagnostic tool such as transesophageal echocardiography (5), found no differences in the prevalence of valvular disease between patients with and without aPL.
The relationship between aPL and the incidence and
outcome of valvular disease is difcult to assess because
most reports had a short (2 years) followup (3,8) or no
followup at all (2,4 6,9). Only 2 series with a longer
followup (5 years) focused on valvular heart disease in
SLE patients have been published until now (1,10), but
neither contained data on aPL.
The aim of this prospective, clinical and echocardiographic study with a long followup (14 years) was to
determine if the presence of aPL is related to the incidence
of severe valvular dysfunction and the need for valve
replacement in an unselected population of SLE patients.

Valvular Regurgitation and aPL in SLE

PATIENTS AND METHODS

Study population. The study population was a cohort of
61 unselected patients (55 women and 6 men; mean SD
age 34 13 years, range 18 68 years) seen consecutively
for the rst time at the Hospital Clinic of Barcelona between 1986 and 1989. The 61 patients either attended as
outpatients (43 patients) or had been admitted due to an
exacerbation of their disease (18 patients). All met the
1982 revised criteria of the American College of Rheumatology (formerly American Rheumatism Association) for
the classication of SLE (11).
According to the study protocol, medical and family
histories were taken and a routine general physical examination was carried out. All patients were specically
questioned about a history of rheumatic fever or infective
endocarditis. No patient was specically referred due to
suspected valvular involvement.
Two-dimensional Doppler echocardiograms were carried out in each patient. In patients with valve thickening
and vegetations, infective endocarditis was excluded by
means of 6 negative blood cultures. According to the original protocol, all patients had a second echocardiogram
scheduled 2 years after the baseline examination. In 1989,
the protocol was modied: the second echocardiogram
was scheduled 2 4 years after the baseline, and it was
recommended that new echocardiograms be repeated every 2 years and when clinically indicated.
All patients were clinically followed by the same medical team for a median of 14 years (mean SD 13.6 3,
range 220 years). Fifty-nine (97%) had a second echocardiographic evaluation performed 2 4 years after the rst.
Two patients died before the second echocardiography
was performed. Forty-eight patients had 2 echocardiographies during followup (mean 4, range 3 6). For these
patients, the last echocardiography performed during the
followup period of the study was considered the followup echocardiography for purposes of comparison.
Median time between rst and followup echocardiography
was 7 years (mean SD 8 3 years, range 214 years).
The initial echocardiographic ndings were compared
with those of 40 healthy age- and sex-matched volunteers
(36 women and 4 men, mean SD age 37 11 years) with
no clinical evidence of cardiac or systemic disorders. The
inclusion of normal controls in the study was considered
appropriate for blinding echocardiographic interpretations.
The study was approved by the Human Research Committee of our institution, and all subjects provided informed consent.
Laboratory studies. Lupus anticoagulant (LAC) was detected using activated partial thromboplastin time, diluted
Russells viper venom time, and tissue thromboplastin
inhibition test. Tests were also performed in mixtures with
control plasmas or phospholipids following the guidelines
of the Subcommittee for the Standardization of Lupus
Anticoagulants of the International Society of Thrombosis
and Haemostasis (12).
Anticardiolipin antibodies (aCL) were measured using a

461
standardized enzyme-linked immunosorbent assay (Chesire
Diagnostics, Chester, UK). Results were expressed in IgG
and IgM units and reported as negative (15 units), low
positive (16 25 units), moderate positive (26 40 units),
and high positive (40 units).
Determinations of IgG and IgM aCL and LAC were performed when the patient was included in the study and 8
weeks later. The treating physician was allowed to repeat
aPL determinations when clinically indicated. During followup, patients had an average of 6 aPL determinations
(SD 3, range 212). Patients with 2 positive determinations for IgG or IgM aCL were considered positive for aCL.
Patients with 2 positive determinations for LAC were
considered positive for LAC.
Antinuclear antibodies were determined by indirect immunouorescence by using mouse liver and HEp-2 cells as
substrate. Anti double-stranded DNA antibodies were determined by Farr ammonium sulfate precipitation technique and indirect immunouorescence with Crithidia luciliae as substrate. Precipitating antibodies to extractable
nuclear antigens, including Ro/SSA, La/SSB, U1 small nuclear RNP and Sm, were detected by counterimmunoelectrophoresis using calf and rabbit thymus and human spleen
extracts. Rheumatoid factor was detected by latex test.
Echocardiographic studies. All subjects underwent initial and followup echocardiography with a color Doppler
imaging system (Hewlett-Packard Sonos 1000 or 2500;
Hewlett-Packard, McMinnville, OR). Multiple 2-dimensional echocardiographic views were taken from the
parasternal, apical, and subcostal positions to determine
the presence of any valve abnormality. Continuous-wave
Doppler examination was carried out in all cases from the
apical position.
To determine the thickness of the mitral, tricuspid, and
aortic valves, all the settings were adjusted at the lowest
intensity that allowed proper recognition of the true valvular structure. The valve leaets were measured with
M-mode echocardiography (10 mm/second) from the longitudinal view (for the mitral valve and the right and
noncoronary cusps of the aortic valve). The left coronary
cusp and the tricuspid valve were measured by 2-dimensional echocardiography from the basilar short axis view
(left coronary cusp) and the 4-chamber view (tricuspid
valve).
In the control subjects, the thickness of the mitral and
tricuspid valves was between 0.7 and 3 mm, and the aortic
valve thickness was 0.72 mm. Abnormal valvular thickening was therefore considered to be present when a thickness of 3 mm (for the mitral and tricuspid valves) or 2
mm (for the aortic valve) was observed.
Valvular vegetation was dened as an abnormal localized echodensity with well-dened borders that was either
part of or adjacent to valve leaets, the subvalvular apparatus, or the great vessels. Pericardial effusion was dened
according to previous publications (13).
Mitral or tricuspid valve regurgitation was graded using
the color Doppler jet-area method (14). Special attention
was focused on the origin and width of the regurgitant jet,
the spatial orientation of the regurgitant jet area in the

462

Perez-Villa et al

Table 1. Frequency of valvular abnormalities on echocardiogram (echo) in patients with

systemic lupus erythematosus (SLE) and controls*

Any valvular abnormality

Valvular regurgitation
Mitral
Aortic
Tricuspid
Valvular stenosis
Mitral
Aortic
Valvular thickening
Mitral
Aortic
Tricuspid
Vegetations

Controls
(n 40)

SLE patients
initial echo
(n 61)

SLE patients
followup echo
(n 59)

2 (5)
2 (5)
2 (5)
-

24 (39)
19 (31)
16 (26)
4 (7)
4 (7)
16 (26)
12 (20)
8 (13)
4 (7)

43 (73)
33 (56)
27 (46)
8 (14)
16 (27)
2 (3)
1
2
29 (49)
23 (39)
11 (19)
2 (3)
4 (7)

* Data are presented as number (%) of patients. Any valvular abnormality valvular thickening,
vegetation, regurgitation, or stenosis.
Two patients died before the followup echocardiogram was performed (both had a normal initial echo).
Some patients had 1 valvular abnormality.
P 0.01 for the comparison between controls and SLE patients (initial echo).
Among SLE patients, P 0.0001 for the comparison between initial and followup echo.
Among SLE patients, P 0.01 for the comparison between initial and followup echo.

receiving chamber, and the ow convergence into the regurgitant orice. To standardize the measurements, we
used a Nyquist limit of 50 60 cm/second and a color gain
that just eliminated random color speckle and background
noise. In this way, we tried to minimize the several factors
affecting the size of the regurgitant area. We considered
trivial mitral regurgitation (small, noneccentric color ow
jets with an area 1.1 cm2) as a normal variant, whereas
mild mitral regurgitation (small, central jet with area 4
cm2 or 20% of LAC area) was classied as a valvular
abnormality (15).
Aortic regurgitation was graded according to the ratio of
the width of the color jet to the diameter of the left ventricular outow tract. The severity of valvular stenosis was
assessed by calculating the valvular area using the continuity equation. All echocardiograms were given a code
number and the studies in patients with SLE were interpreted in random order together with those of normal
controls.
Two experts in echocardiography assessed all studies
without knowledge of the patients status or the timing of
the studies.
Statistical analysis. Conventional chi-square and Fishers exact tests were used to analyze qualitative differences. The students t-test was used for comparison of
means in large samples of similar variance, and the nonparametric Mann-Whitney U test was used for small samples. A 2-tailed P value 0.05 was considered statistically
signicant.

RESULTS
Baseline characteristics of the patients. The 61 patients
had a mean SD SLE duration of 4 3 years (range 114

years) at study enrollment. Thirty-ve (57%) patients had

no aPL, 5 (8%) had LAC, 8 (13%) had aCL, and 13 (21%)
had both LAC and aCL. Eight patients with aPL had a
history of arterial thrombosis, venous thrombosis, or recurrent pregnancy loss.
None of the 40 controls had a positive titer of aCL or
LAC activity.
Valvular abnormalities at baseline and followup. Table
1 shows the main echocardiographic ndings in SLE patients at baseline and followup. Valvular abnormalities
were present in the initial echocardiogram in 39% of the
patients with SLE and in 5% of the controls (P 0.01). The
mitral valve was the most commonly affected, followed by
the aortic and tricuspid valves. Valvular regurgitation was
the most common abnormality, being detected in 31% of
patients at the initial echocardiogram. Mitral regurgitation
was seen in 26% of patients, aortic regurgitation in 7%,
and tricuspid regurgitation in 7% of patients. No valvular
stenosis was detected at the rst echocardiography.
Valvular thickening was seen in 26% of the patients at
the rst echocardiographic study. Valvular vegetations
were present in 7% of patients. In all patients, they were
located on the mitral leaets.
Two control subjects had mitral valve prolapse with
mild mitral regurgitation.
At the followup echocardiogram, 73% of SLE patients
had valvular abnormalities (Table 1). Compared with the
baseline echocardiography, there was a signicant increase in mitral valve thickening, mitral regurgitation, and
tricuspid regurgitation (P 0.01). Two patients had developed a mild or moderate valvular stenosis (aortic in one
patient, mitral and aortic in the other) at followup.
The percentage of patients with pericardial effusion
(25% versus 17%) and the end-diastolic (mean SD 50

Valvular Regurgitation and aPL in SLE

463

Table 2. Changes in valvular regurgitation between initial and followup

echocardiography (echo)

Mitral regurgitation
Mild
Moderate
Severe
Total
Aortic regurgitation
Mild
Moderate
Severe
Total
Tricuspid regurgitation
Mild
Moderate
Severe
Total

Initial echo
(n 61)

Lesions
improved

Lesions
worsened

New
lesions

Followup echo
(n 59)*

10
3
3
16

2
1
3

1
2
3

12
1
13

20
1
6
27

3
1
4

4
4

7
1
8

3
1
4

1
1
2

12
1
13

14
2
16

* Two patients without valvular regurgitation died before the followup echo.
Two patients with moderate lesions worsened to having severe lesions.

5 mm versus 51 2 mm) and end-systolic (31 5 mm

versus 29 5 mm) diameters of the left ventricle did not
change between the rst and the followup echocardiographies. The left ventricle ejection fraction showed a mild
yet signicant decrease (66 7% versus 62 9%, rst
versus followup echocardiographies; P 0.05).
Changes in valvular regurgitation. During followup,
there were changes in the severity of valvular regurgitation
(Table 2). In 5 patients, regurgitation improved; in 3 patients, regurgitation worsened; and in 30 (51%) patients, a
new valvular regurgitation appeared.
Seven patients had severe valvular regurgitation at the
end of followup: 4 were already severe at the rst echo, 2
were moderate and worsened during followup, and 1 with
a nonregurgitant valve in the rst echocardiography developed a new severe regurgitation. Interestingly, none of the
patients with severe mitral or aortic regurgitation on the
rst echocardiography showed improvement. Only one
case of severe tricuspid regurgitation improved to moderate in the followup echocardiography: this was a patient
with severe pulmonary hypertension, right ventricular dilation, and secondary tricuspid insufciency.
Age, duration of SLE, years of followup, medications
(including oral anticoagulants and aspirin), and aPL were
not signicantly different between patients with new or
worsening valvular lesions and those with stable or improving valvular lesions. IgM aCL, however, was signicantly more prevalent among patients with new or worsening valvular regurgitation (24% of patients with IgM aCL
versus 4% in the group with stable or improved valvular
lesions; P 0.03).
We could not see a time-related pattern of development
of valvular disease in SLE patients.
Patients with and without severe valvular regurgitation. In Table 3, the baseline characteristics of the 7 patients who developed severe mitral or aortic regurgitation

are compared with the 52 patients who did not. Patients

with severe valvular regurgitation showed a trend toward
younger age than patients without severe regurgitation;
there were no differences in SLE duration, SLE disease
manifestations, or SLE activity. Antiplatelet therapy was
more frequently prescribed in patients with severe valvular disease, although in most cases (6 of 8), this therapy
was started after the diagnosis of valvular regurgitation
had been made.
Patients with severe valvular regurgitation were more
likely to have aPL (P 0.01). Both LAC (P 0.02) and aCL
(P 0.003) were signicantly more prevalent in patients
with severe valvulopathy (Table 3). The association between high titers of IgG aCL and the presence of severe
valvular regurgitation was highly signicant (P 0.001)
(Figure 1).
We found no association between severe valvulopathy
and the presence of other autoantibodies.
Valvular surgery. During the 14 years of followup,
valve replacement was required by 5 patients with severe
valvular regurgitation (4 mitral, 1 aortic) (Table 4). There
was a strong association between the presence of high
levels of IgG aCL and the need for valve surgery: all 5
patients that required valvular surgery had high titers of
IgG aCL. Four had a history of previous arterial thrombosis, associated with venous thrombosis in 1 patient and
with recurrent pregnancy loss in another patient.
In all cases, surgery was indicated in symptomatic patients with New York Heart Association functional class II
or III, severe valvular regurgitation, moderate left ventricular dysfunction (ejection fraction 0.30 0.50), and endsystolic dimension 50 55 mm. In all patients, surgery
consisted of valve replacement by a bileaet mechanical
valve.
Thromboembolic events. Four patients had thromboembolic events after valvular surgery. One patient died

464

Perez-Villa et al

Table 3. Baseline characteristics of the patients with and without severe mitral or aortic
regurgitation*

Age, mean SD years

Duration of SLE, mean SD years
Active SLE, %
Medications, no. (%)
Corticosteroids
Chloroquine
Azathioprine
Cyclophosphamide
Oral anticoagulants
Aspirin
Antiphospholipid antibodies, no. (%)
Lupus anticoagulant
Anticardiolipin antibodies

Severe valvular
regurgitation
(n 7)

Without severe
valvular
regurgitation
(n 52)

25.2 8
6.8 5
60

35.1 13
4.0 4
56

0.05
NS
NS

21 (40)
9 (17)
6 (12)
14 (27)
5 (10)
5 (10)
17 (33)
13 (25)
13 (25)

NS
NS
NS
NS
NS
0.05
0.01
0.023
0.003

5 (71)
0
3 (43)
1 (14)
1 (14)
3 (43)
6 (86)
5 (71)
6 (86)

* SLE systemic lupus erythematosus; NS not signicant.

due to acute thrombosis of a mitral valve prosthesis 2

months after surgery, and the remaining 3 had a cardioembolic ischemic stroke, a transient ischemic attack, and a
peripheral embolism, respectively. All were anticoagulated with coumadin without concomitant antiplatelet
therapy (which was started after the ischemic event in the
3 survivors). Two patients had an International Normalized Ratio 2.0 when they suffered the thrombotic event.
Overall, thromboembolic events were signicantly more
frequent (P 0.026) in patients with than in patients
without severe valvular disease (Table 4).
Mortality. During the 14 years of followup, 9 patients
died. The causes of death were as follows: septic shock (3

patients), infective endocarditis (in a patient with no valvular abnormalities in the echocardiogram performed 3
years earlier), recurrent pulmonary embolism, chronic renal failure plus hyperkalemia, chronic renal failure plus
gastrointestinal hemorrhage, catastrophic antiphospholipid syndrome with multiple thrombotic episodes, and a
thrombosis of the mitral valve prosthesis.
Mortality was not different between patients with and
without severe valvulopathy. However, the combined incidence of thromboembolic events (stroke or peripheral
embolism), valve surgery, or death was signicantly higher
(P 0.003) in patients with severe valvular regurgitation
(Table 4).

DISCUSSION

Figure 1. Prevalence of severe valvular regurgitation in patients

with systemic lupus erythematosus, according to their plasma
levels of IgG anticardiolipin antibodies. aCL anticardiolipin
antibodies; IgG low levels of IgG; IgG moderate levels of
IgG; IgG high levels of IgG.

To our knowledge, this is the rst report of a long-term

followup study of SLE-associated valvular heart disease to
include data on aPL. It is also the rst study to focus
specically on severe, clinically signicant valvular disease in patients with SLE. Previous reports have described
an association between aPL and the presence of any valvular abnormality (29). In our series, the number of patients with any valvular abnormality increased from 40%
to 70% over 10 years of followup, suggesting that over a
long period, a substantial majority of patients will develop
valvulopathy. A more sensitive diagnostic tool, such as
transesophageal echocardiography, would probably have
revealed that nearly all SLE patients (both with and without aPL) would have shown valvular abnormalities, basically valvular thickening with mild regurgitation.
However, not all valvular abnormalities have the same
clinical signicance. In our series, after 14 years of followup, only 12% of SLE patients had a severe valvular
regurgitation causing left ventricular dysfunction and
symptoms of heart failure. In this signicant minority of
patients, the valvular damage appears earlier, is more severe, and does not improve over time. These patients with

Valvular Regurgitation and aPL in SLE

465

Table 4. Prevalence of thromboembolic events (stroke or peripheral embolism), valvular

surgery, and death in patients with and without severe mitral or aortic regurgitation
Severe valvular
regurgitation
(n 7)

Without severe
valvular
regurgitation
(n 52)

5 (71)
4 (57)
2 (29)
6 (86)

0
8 (15)
7 (14)
13 (25)

0.0001
0.026
NS*
0.003

Valvular surgery, no. (%)

Thromboembolic event, no. (%)
Death, no. (%)
Any of the previous, no. (%)
* NS non signicant.

SLE and severe valvular disease have a high incidence of

thromboembolic events and often need valvular surgery.
They should be identied early and followed closely by
serial echocardiographic examinations.
The development of severe valvular regurgitation was
associated with the presence of aPL and, more specically,
with the presence of high levels of IgG aCL. We found no
association with the duration, activity, or treatment of
lupus. Patients with severe regurgitation were slightly
younger than patients with less severe valvular affectation,
suggesting that degenerative valvular disease associated
with aging does not explain the more severe valvular damage in this group of SLE patients. Our results suggest that
high levels of IgG aCL are the most sensitive marker for the
detection of SLE patients at high risk of developing severe
valvular regurgitation.
A limitation of our study is the small number of patients
with severe valvular disease. Nevertheless, this is a consequence of the low prevalence of severe valvular disease
in SLE patients.
In our series, 5 of 7 patients who developed severe
valvular regurgitation required valvular surgery. In all 5
cases, a valvular replacement was performed and a bivalve
mechanical prosthesis was implanted. Reports of valvular
surgery in SLE patients are scarce: only about 50 cases
have been reported, mostly individual case reports (16
46). Our series of 5 patients is the same size as the largest
previously published (41). Although mitral valve repair
and mitral valve substitution by a biologic prosthesis or a
homograft have been described, mitral valve replacement
by a mechanical prosthesis accounts for the majority of
surgical procedures in SLE patients.
We found that high levels of IgG aCL were strongly
associated with the need for valvular surgery. This is clinically relevant because the risk of thromboembolic events
may be signicantly increased in patients with a mechanical prosthesis and circulating aPL (47,48). In fact, 4 of our
patients had thromboembolic events after surgery. The
antithrombotic strategy in these cases should include the
combination of warfarin and aspirin, according to the recommendations of the American Heart Association for patients with a high risk of thrombosis (49).
Lockshin et al have recently reviewed the treatment for
valve disease in patients with antiphospholipid antibody
syndrome (50). Undoubtedly, the best therapeutic approach for lupus valvulopathy would be to prevent the

development of severe valvular damage. Our ndings suggest that a local thrombotic mechanism might participate
in the pathophysiology of valvular damage in those SLE
patients who develop severe valvular regurgitation. However, we found no association between treatment with
anticoagulants or antiplatelet drugs and the development
of severe valvulopathy, probably due to the small number
of patients who received warfarin or aspirin before the
diagnosis of severe valvulopathy had been made.
In conclusion, we found that the development of severe
valvular regurgitation in SLE patients over a long followup
period is associated with the presence of high levels of IgG
aCL and with a high incidence of need for valvular surgery
and thromboembolic events. In this high-risk group of
patients, close clinical and echocardiographic followup is
recommended and a more aggressive anticoagulant or antiplatelet therapy aimed at preventing valvular damage
may be benecial.

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