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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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