Download Is the heart affected in primary Sjögren`s syndrome? An

Clinical and Experimental Rheumatology 2008; 26: 109-112.
Is the heart affected in
primary Sjögren’s
syndrome? An
echocardiographic study
V.A. Vassiliou, I. Moyssakis,
K.A. Boki, H.M. Moutsopoulos
Department of Pathophysiology,
University of Athens School of Medicine,
(V.A.V., H.M.M.), the Rheumatology
Department of Athens General Hospital
“SISMANOGLEIO” (K.A.B.), and the
Cardiology Department of Athens General
Hospital “LAIKO”, Athens, (I.M.), Greece.
Vassilios A. Vassiliou, MD; Ioannis
Moyssakis, MD; Kyriaki A. Boki, MD;
Haralampos M. Moutsopoulos, MD.
Please address correspondence to:
Vassilios A. Vassiliou, MD, Department
of Pathophysiology, University of Athens
School of Medicine, 75 M. Asias St,
Athens, 11527, Greece.
E-mail: [email protected]
Received on February 12, 2007; accepted
in revised form on June 7, 2007.
© Copyright CLINICAL AND
EXPERIMENTAL RHEUMATOLOGY 2008.
Key words: Primary Sjögren’s
syndrome, heart involvement.
Competing interests: none declared.
BRIEF PAPER
ABSTRACT
Objective. To evaluate whether patients
with primary Sjögren’s
’’s syndrome without overt cardiac disease have echocardiographic abnormalities and their relation with clinical and laboratory data.
Methods. One hundred and seven
consecutive patients with primary Sjögren’s
’’s syndrome and 112 healthy controls, matched for age and gender, underwent complete echocardiographic
study.
Results. Thirty-two patients had mitral valve regurgitation (p < 0.001)
whereas tricuspid and aortic valve regurgitation were, also, more frequent
in the patient group (p = 0.022 and p
= 0.007 respectively). In multivariate
analyses, low C4 levels of complement
and age were strong predictors of mitral valve regurgitation whereas age
was predictor of aortic valve regurgitation. Tricuspid valve regurgitation was
associated with pulmonary hypertension. Clinically silent pericardial effusion, found in 9 patients (p = 0.008),
was associated with cryoglobulinemia
and primary biliary cirrhosis. Twentyfour patients had pulmonary hypertension (p < 0.001) whereas hypocomplementemia and cryoglobulinemia were
strong predictors of pulmonary artery
systolic pressure. The analyses reveal
that easy fatigability was associated
with pulmonary hypertension and low
C4 levels. The patients’’ left ventricular mass index differed significantly
from the controls (108.9 ± 17.21gm-2
vs. 85.8 ± 6.73gm-2, p < 0.001) and
was associated with palpaple purpura
and anti-Ro/SSA. From the diastolic function indices only the left ventricular isovolumic relaxation time
differed significantly among patients
and controls.
Conclusion. Valvular regurgitation,
pericardial effusion, pulmonary hypertension and increased left ventricular
mass index occur with disproportionately high frequency in patients with
primary Sjögren’s
’’s syndrome and no
clinically apparent heart disease. Thus
echocardiographic studies may need
to be performed in these patients especially when palpable purpura, antibody reactivity and low C4 levels are
present.
109
Introduction
Cardiac involvement is not well established in primary Sjögren’s syndrome,
a chronic autoimmune exocrinopathy
that affects mostly middle-aged women
leading to xerostomia and keratoconjunctivitis sicca. In more than one third
of the patients the autoimmune process
involves extraglandular sites with lymphoproliferative malignancy being its
most frightening complication. Small
series and case reports have already
reported pericarditis, systolic and diastolic dysfunction of the left ventricle, valve disorders and autoimmune
myocarditis (1-5). Moreover, evidence
demonstrates association of morbidity
and mortality from the syndrome with
clinical rheumatic and serological findings. Low C4 levels and/or palpable
purpura are two characteristics that
may classify patients (1 to 5) who are
in increased risk for lymphoproliferative disease and death (6).
This echocardiographic study aimed to
describe the anatomic and functional
cardiac disorders in asymptomatic patients with primary Sjögren’s syndrome
in comparison with healthy subjects,
and to evaluate whether these findings
were associated with rheumatic manifestations and immunological indices.
Patients and methods
Patients
Two hundred and nineteen subjects with
normal electrocardiogram were evaluated by echocardiography. One hundred seven consecutive patients (103
women, mean age 56.5 ± 12.5 years,
mean disease duration 7.5 ± 4.9 years
and median 6.0 years) with primary
Sjögren’s syndrome biopsy documented and according to the American-European consensus criteria of the classification of the disease were studied (7).
One hundred twelve healthy subjects,
visitors to the hospital (108 women,
mean age 55.4 ± 12.2 years, p = 0.495
compared with patients), without history of cardiovascular disease having
normal physical examination served as
the control group. All study participants
gave informed consent and the study
was conducted in accordance with the
ethical guidelines of our institution.
Exclusion criteria for both groups were
BRIEF PAPER
documented myocardial infarction, previous history of rheumatic fever, arterial
hypertension, atrial fibrillation, hypertrophic cardiomyopathy, lipidemia, diabetes mellitus or metabolic syndrome.
Echocardiographic evaluation
Comprehensive echocardiographic examination with pulsed, continuous and
color Doppler was performed with a
Hewlett Packard Sonos 1.000 ultrasound system, using a 2.5 MHz transducer. Left-ventricular end-systolic and
end-diastolic diameters as well as interventricular septum and posterior wall
thickness at end-diastole were measured
for calculation of the fractional shortening and left-ventricular mass with the
Penn convention formula (8, 9). Measurements of left-ventricular mass were
divided by body surface area to obtain
left-ventricular mass index. Right ventricular systolic function was evaluated
from the tricuspid annular plane systolic excursion (TAPSE) (10). Pulmonary
artery systolic pressure (PASP) was
estimated by continuous wave Doppler
echocardiogram as the peak systolic
pressure gradient across the tricuspid
valve plus the estimated right atrial
pressure (11). Pulmonary artery pressure above 35mmHg was considered as
pulmonary hypertension (12).
Using pulsed Doppler from the mitral
and tricuspid inflow velocity curves the
following parameters were calculated:
peak early velocity (E-wave), peak velocity at the time of atrial contraction
(A-wave), E/A ratio, deceleration time
of the peak early velocity and the isovolumic relaxation time (13).
Valve structure and function were examined using the Doppler method beginning with color flow imaging. When abnormal intracardiac flow was detected,
pulsed and continuous wave Doppler
studies were performed. Regurgitation
severity grading was semi-quantitative
and based on the size and duration of
the transvalvular jet (14).
Clinical and laboratory data
Arthritis or arthralgias, Raynaud’s phenomenon, palpaple purpura, lymphadenopathy, splenomegaly, lung disease
(carbon monoxide diffusing capacity <
70% of predicted, and/or ground glass
Echocardiographic features in primary Sjögren’s syndrome / V.A. Vassiliou et. al.
appearance in computed tomography
scan), interstitial nephritis (persistently
alkaline urine with pH > 7, serum bicarbonate < 19mEq/dl and/or biopsy
documented), glomerulonephritis (proteinuria > 500mg/dl or cellular casts
and documentation by renal biopsy),
peripheral neuropathy (physical examination and nerve conduction studies)
and primary biliary cirrhosis (biopsy
documented) were collected from the
patients’ medical records.
Additionally, we collected information
on the following laboratory parameters:
rheumatoid factor (IgM latex fixation,
positive titer ≥ 40), antinuclear antibodies, antimitochondrial antibodies, anticentromere antibodies (immunofluorescence), antibodies to extractable nuclear
antigens Ro/SSA and La/SSB (counterimmunoelectrophoresis), C3 and C4
components of complement (nephelometry) and serum cryoglobulins. Antibodies to Cardiolipin were measured
by ELIZA using cardiolipin (Sigma
1649) as antigen on polystyrene plates.
Erythrocyte sedimentation rate, serum
levels of C-reactive protein, total, HDL
and LDL cholesterol and triglycerides
measured by standard methods were
available for all the subjects during the
preceding month.
Comparisons and statistical methods
Statistical analysis was performed using SPSS statistical package. Student’s
t-test was used to assess differences
in continuous variables, while a chisquare test was used for categorical
variables. Correlation coefficients were
estimated, univariate and multivariate
logistic or linear regression analyses
were performed in the patient population to evaluate whether clinical and
laboratory characteristics are associated
with the echocardiographic findings.
Values are expressed as mean ± 1 standard deviation. A p-value less than 0.05
was considered significant. P-values are
two-tailed.
Results
The clinical manifestations of cases
and the autoantibodies found were
typical of a cohort of patients with this
syndrome. Thirty-two ((p < 0.001) patients had mitral valve regurgitation
which was mild in all patients and in 4
patients it was due to mitral valve prolapse. Aortic regurgitation was present
in 25 patients ((p = 0.007) and was mild
in all cases while in 2 patients, it coexisted with mild aortic stenosis. Tricuspid regurgitation was seen in 11
patients ((p = 0.022) and in 3 cases it
was of moderate severity. Moreover,
a small amount of pericardial effusion
was found in 9 patients ((p = 0.008) who
did not report or have any symptom or
sign of pericarditis. The left-ventricular mass index of the patients differed
significantly from the controls (108.9
Table I. Two-dimensional and Doppler echocardiographic findings, left and right ventricular
systolic and diastolic parameters.
Parameters
Patients with pSS
Mitral regurgitation
Aortic regurgitation
Tricuspid regurgitation
Pericardial effusion
Pulmonary hypertension
LV mass index (g/m2)
Fractional shortening (%)
TAPSE (mm)
LV E/A
LV DT (ms)
LV IVRT (ms)
RV E/A
RV DT (ms)
RV IVRT (ms)
32 / 107
25 / 107
11 / 107
9 / 107
24 / 107
108.93 ± 17.21
35.84 ± 4.4
16.21 ± 1.13
0.98 ± 0.21
164 ± 21
87 ± 11.4
1.06 ± 0.18
161 ± 19.8
52.4 ± 3.1
Controls
12 / 112
11 / 112
3 / 112
1 / 112
0 / 112
85.81 ± 6.73
36.55 ± 3.9
16.42 ± 1.04
1.01 ± 0.12
161 ± 19
76.4 ± 8.6
1.09 ± 0.15
158.9 ± 16.4
51.8 ± 3.5
p-value
< 0.001
0.007
0.022
0.008
< 0.001
< 0.001
NS
NS
NS
NS
< 0.001
NS
NS
NS
LV: left ventricular; RV: right ventricular; TAPSE: tricuspid annular plane systolic excursion;
E/A: ratio of E wave to A wave; DT: deceleration time; IVRT: isovolumic relaxation time.
110
Echocardiographic features in primary Sjögren’s syndrome / V.A. Vassiliou et. al.
Table II. Predictors of valvular regurgitation, pulmonary hypertension, pericardial effusion
and increased left ventricular mass index.
Echocardiographic finding
Clinical & laboratory
characteristics
Odds ratio (95%
confidence interval)
p-value (B)
Mitral valve regurgitation
Pulmonary hypertension
Age
Low C4
3.98 (1.54-10.32)
1.04 (1.01-1.08)
3.31 (1.12-9.79)
0.0045 (1.38)
0.022 (0.043)
0.031 (1.196)
Aortic valve regurgitation
Age
Pulmonary hypertension
1.10 (1.05-1.15)
3.24 (1.21-8.67)
< 0.001 (0.009)
0.019 (1.175)
Tricuspid valve regurgitation Articular Disease
Lung Disease
Pulmonary hypertension
0.13 (0.03-0.54)
3.83 (1.0-14.69)
13.33 (3.19-55.79)
0.005 (-2.056)
0.05 (1.344)
0.0004 (2.590)
Pericardial effusion
Primary biliary cirrhosis
Liver disease
Cryoglobulinemia
Hypocomplementemia
8.57 (1.59-46.20)
6.95 (1.40 – 34.52)
6.89 (1.17-40.71)
5.07 (1.13 – 22.72)
0.012 (2.148)
0.017 (1.939)
0.033 (1.93)
0.034 (1.624)
Pulmonary hypertension
Easy fatigue
Primary biliary cirrhosis
6.42 (1.66-24.83)
6.38 (1.61-25.27)
0.007 (1.859)
0.008 (1.852)
PASP
Hypocomplementemia
Cryoglobulinemia
Interstitial nephritis
Lung disease
20.19 (10.43 – 29.96) < 0.001 (0.625)
17.17 (8.01 – 26.32)
0.001 (0.620)
13.85 (2.54 – 25.15)
0.018 (0.428)
9.69 (0.36 – 19.02)
0.042 (0.373)
LV mass index
Xerostomia
Rheumatoid factor
Purpura
Low C3
Anti-Ro/SSA
16.28 (5.50-27.06)
9.06 (2.69-15.42)
10.79 (2.46-19.13)
17.35 (1.15-33.56)
6.65 (0.18-13.12)
0.003 (0.297)
0.006 (0.280)
0.012 (0.258)
0.036 (0.253)
0.044 (0.207)
LV mass index: left ventricular mass index; Articular Disease: arthritis/arthralgias; PASP: pulmonary
artery systolic pressure. Negative values mean that the respective echocardiographic finding is reduced
in the presence of the predictor. In the second column, only potentially important predictors with p <
0.05 are shown.
± 17.21 gm-2 vs. 85.8 ± 6.73 gm-2, p <
0.001, Table I).
Twenty-four patients (22.4%, p<0.001)
had pulmonary hypertension, which was
mild in 21 patients whereas in 3 cases
the PASP was greater than 50mmHg.
There were no significant differences in
left and right ventricular systolic function indices whereas from the indices
of diastolic function only the left-ventricular isovolumic relaxation time was
different between patients and controls
but did not have any statistically important correlation (Table I).
In multivariate regression analyses (Table II), low C4 levels (Beta = 0.364, p =
0.003) and age (Beta = 0.294, p = 0.016)
were strong predictors of mitral valve
regurgitation. Similarly, the age of the
patients (Beta = 0.400, p < 0.001) was
associated with aortic valve regurgitation in multivariate analyses, and the
presence of pulmonary hypertension
(Beta = 0.464, p < 0.001) with tricuspid valve regurgitation. Additionally,
hypocomplementemia (Beta = 0.410, p
= 0.026) and cryoglobulinemia (Beta =
0.404, p = 0.028) were associated with
PASP values whereas cryoglobulinemia
(Beta = 0.294, p = 0.006) and primary biliary cirrhosis (Beta = 0.221, p =
0.037) were strong predictors of pericardial effusion. The presence of antiRo/SSA antibodies in the sera (Beta =
0.289, p = 0.014) and palpable purpura
(Beta = 0.258, p = 0.027) were associated with increased left ventricular mass
index.
Discussion
Even though valve disorders have previously been observed in patients with
primary Sjögren’s syndrome, the exact
effect and clinical association of these
are unclear (1, 2). We clearly show that
these patients had more often than controls mild mitral, aortic and tricuspid regurgitation. The particularly increased
proportion of mitral and aortic valve regurgitation in patients and controls may
111
BRIEF PAPER
be due to their increased age• approximately, 70% of the subjects were over
50 years old. In this study, mitral valve
regurgitation was associated with the
presence of low C4 levels of the complement which may reflect a pathogenesis
of the valve tissue lesions involving the
activation of the classical complement
pathway through immune complexes,
and consequently the extraglandular inflammatory process causing fibrosis of
the valve structures or may be surrogate
marker for this process.
Pulmonary hypertension was present
in 20% of the patients and was mild
with the exception of 3 cases where
the pulmonary artery systolic pressure
was greater than 50mmHg. Pulmonary
hypertension is a common finding in
autoimmune diseases, but it has been
poorly documented in these patients
in previous studies (1). Our analyses
suggested that the presence of pulmonary hypertension in patients with primary Sjögren’s syndrome may be associated with lung disease, interstitial
nephritis, hypocomplementemia and
cryoglobulinemia. Respiratory system
and kidneys are usually affected mildly
in primary Sjögren’s syndrome, but interstitial disease is the reason for severe
symptoms· only one out of the three patients with severe pulmonary hypertension had interstitial lung disease (15).
Although pulmonary hypertension and
associated right heart failure are important consequents of lung disease and
pulmonary fibrosis, our analyses did
not reveal significant associations. Consequently, only hypocomplementemia
and cryoglobulinemia, who are probable indices of immunological reactivity,
may play a predictive role in pulmonary
hypertension.
Only 9 of the 107 patients had a small
amount of pericardial effusion which
caused no significant hemodynamic
changes. Pericardial effusion was associated with cryoglobulinemia and
primary biliary cirrhosis. Our results
are in line with previous studies which
suggest pericardial inflammation in the
process of the disease (1, 2).
The left-ventricular mass index in this
study was on average greater in patients
than in controls. The observed association with anti-Ro/SSA and purpura
BRIEF PAPER
suggest that systemic vasculitis or the
disease activity with the autoantibody
profile may play a role in the pathway
of the increase in left-ventricular mass
index (3-5). Furthermore, the blocking
of capillary vessels by the circulating
immune complexes, the consequent
local ischemia and inflammation may
affect the myocardium either through
vasculitis of the vasa vasorum or the
coronary vasospasm (analogous to myocardial Raynaud’s phenomenon) or
through microcirculation abnormalities
that may cause pressure overload (1).
In conclusion, our study shows that silent cardiac involvement is fairly common in patients with primary Sjögren’s
syndrome. Although most of the lesions were relatively mild, their clinical impact is unknown and it is unclear
whether these lesions may be evolving
over time to cause overt cardiomyopathy or severe valvular lesions in selected patients. Based on the above data,
echocardiographic studies may need to
be considered in patients with palpable
purpura, autoantibody reactivity and
low C4 levels that are at increased risk
of heart involvement.
Echocardiographic features in primary Sjögren’s syndrome / V.A. Vassiliou et. al.
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