Rheumatol Int (2007) 27:813–818 DOI 10.1007/s00296-007-0307-8
O R I G I N A L A RT I C L E
P wave dispersion in patients with rheumatoid arthritis: its relation with clinical and echocardiographic parameters Hayal Guler Æ Ergun Seyfeli Æ Gunsah Sahin Æ Mehmet Duru Æ Ferit Akgul Æ Hayrettin Saglam Æ Fatih Yalcin
Received: 16 June 2006 / Accepted: 1 January 2007 / Published online: 13 March 2007 Springer-Verlag 2007
Abstract P wave dispersion (PWD) is a sign for the prediction of atrial fibrillation (AF). The aim of this study was to assess P wave dispersion and its relation with clinical and echocardiographic parameters in patients with rheumatoid arthritis (RA). Thirty RA patients (mean age 49 ± 10 years) and 27 healthy controls (mean age 47 ± 8 years) were included in the study. We performed electrocardiography and Doppler echocardiography on patients and controls. Maximum and minimum P wave duration were obtained from electrocardiographic measurements. PWD defined as the difference between maximum and minimum P wave duration was also calculated. Maximum P wave duration and PWD was higher in RA patients than
H. Guler (&) Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Mustafa Kemal University, Tip Fak. Arastirma Hastanesi, Bag˘riyanik mah, Ormanci cad, P.K. 3100, Antakya/Hatay, Turkey e-mail:
[email protected] E. Seyfeli F. Akgul F. Yalcin Department of Cardiology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey e-mail:
[email protected] G. Sahin Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Mersin University, Mersin, Turkey M. Duru Department of Emergency Medicine, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey H. Saglam Department of Cardiology, Faculty of Medicine, Afyon Kocatepe University, Afyonkarahisar, Turkey
controls (P = 0.031 and P = 0.001, respectively). However, there was no significant difference in minimum P wave duration between the two groups (P = 0.152). There was significant correlation between PWD and disease duration (r = 0.375, P = 0.009) and isovolumetric relaxation time (r = 0.390, P = 0.006). P wave duration and PWD was found to be higher in RA patients than healthy control subjects. PWD is closely associated with disease duration and left ventricular (LV) diastolic dysfunction. Keywords Rheumatoid arthritis Electrocardiography P wave dispersion Atrial fibrillation Echocardiography
Introduction Rheumatoid arthritis (RA) is a chronic multisystemic disease. Although the rate of mortality due to cardiovascular disease and ischemic heart disease in both sexes is high in RA, cardiac involvement is not always symptomatic in RA [1, 2]. Pericarditis, myocarditis, endocarditis, coronary vasculitis, conduction system abnormalities and valvular disease are among the various cardiac manifestation of this disease [3]. Cardiac repolarization abnormalities may be seen due to cardiac involvement in RA. Recently, several studies associated with QT dispersion have been reported in patients with RA. QT dispersion is a determinant of ventricular arrhythmias [4, 5]. However, P wave duration and P wave dispersion (PWD) have not been studied in RA patients yet. PWD, defined as the difference between maximum and minimum P wave duration, is an electrocardiographic (ECG) marker
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that has been used to evaluate the discontinuous propagation of sinus impulses and the prolongation of atrial conduction time [6–8]. Furthermore, it has been recently defined as a new marker for the prediction of atrial fibrillation (AF) [6]. We hypothesized that the patients with RA may be not only under the risk for ventricular arrhythmias but also under the risk for atrial arrhythmias. Therefore, this study was planned to investigate the P wave duration and PWD in RA patients and to evaluate their relation with clinical findings and echocardiographic parameters.
global score (0–100), and swollen and tender joint counts (both 0–28). This score was calculated as previously described. High activity of disease was defined as a DAS 28 > 5.1, moderate activity of disease was defined as a 3.2 < DAS 28 < 5.1 and low activity of disease was defined as a DAS 28 £ 3.2 [11]. Patients were asked to fill in the Stanford Health Assessment Questionnaire (HAQ) to measure their functional capacity. Height and weight were directly measured by using a standardized protocol. BMI was calculated by dividing weight in kilograms by the square of the height in meters.
Materials and methods
Echocardiographic measurements
Forty patients with RA who were admitted to the department of physical medicine and rehabilitation outpatient clinic were included in this study. All of the patients with RA were diagnosed according to the 1987 revised criteria of the American Rheumatism Association [9]. Physical examination, medical history of patients and blood biochemistry were evaluated in all groups to exclude systemic diseases. Patients with thyroid dysfunction, anemia, electrolyte imbalance, hypertension (HT), diabetes mellitus (DM), heart failure, rheumatic valve disease, primary cardiomyopathy, chronic lung disease, coronary artery disease (CAD) and left bundle branch block, atrioventricular conduction abnormalities on ECG were excluded from the study. All of the patients were in sinus rhythm and none of them were taking medications like antiarrhythmics, tricyclic antidepresants, antihistaminics and antipsychotics. Ten patients, two of them with coronary artery disease, four with HT, two with severe valve disease and two with DM were excluded from the study. Therefore, totally 30 RA patients (28 females, 2 males; mean age 49 ± 10 years) and 27 healthy subjects (24 females, 3 males; mean age 47 ± 8 years) as control group were included in this study. C-reactive protein (CRP, mg/dl) was determined by the nephelometric method and erythrocyte sedimentation rate (ESR, mm/h) was determined by the Westergren method. Rheumatoid factor (RF, IU/ml) was determined by nephelometric method and RF was positive in RA patients (RF > 20 IU/ml). RA disease duration, duration of morning stiffness, number of swollen joints, oral steroid intake (current or past), current antirheumatic drug treatment and RA functional class (Steinbrocker) were recorded [10]. Disease activity was assessed according to disease activity score including 28 joint (DAS 28). Components of DAS 28 are erythrocyte sedimentation rate, patient-assessed
In all subjects, two-dimensional, M-mode, pulsed and color flow Doppler echocardiographic examinations (Vivid 7 pro, GE, Horten, Norway, 2–4 mHz phased array transducer) were performed by the same examiner. The patients were requested to rest for 5 min before the measurements and breathe slowly during the procedure. The examination was performed with the subjects in the left lateral decubitis position with normal breathing. Internal left ventricular (LV) enddiastolic and end-systolic diameters and ventricular septal and posterior wall thickness at end-diastole, and left atrial dimension (LAD) were measured from parasternal long axis window in M-mode echocardiography. The ejection fraction of the left ventricle was obtained using Teichholtz in M-mode echocardiography [12]. The LV mass (LVM) was calculated according to Devereux formula [12]:
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LVM (g) ¼ 0:8 ½1.04 [(PWT þ IVS þ LVEDDÞ3 ðLVEDDÞ3 þ 0.6 where PWT is posterior wall thickness, IVS is ventricular septal wall thickness, and LVEDD is left ventricular end-diastolic dimension. Conventional Doppler echocardiography Early (E) wave, late (A) wave, early to late (E/A) ratio and E deceleration time (E dec) of left ventricular inflow velocities were measured by pulse wave Doppler placing the sample volume in between the tips of the mitral valve leaflets in apical fourchamber window. Isovolumetric relaxation time (IVRT) was obtained from the apical-five-chamber view by placing the sample volume between the tip of the mitral anterior leaflet and left ventricle outflow tract.
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Electrocardiography
Statistical analyses
The 12-lead ECG was recorded at a paper speed of 25 mm/s and gain of 10 mm/mV (Cardiofax V, Nihon Kohden Corp., Tokyo, Japan) in the supine position and were breathing freely but not allowed to speak during the electrocardiographic recording. To avoid from diurnal variations, we generally took the ECG recordings of all RA patients and control subjects at the same time interval (1000–1200 hours). All of the ECGs were transferred to a personal computer (PC) via a scanner and then used for magnification of 400 times by Adobe Photoshop software. The starting point of P wave was referred as the positive deflection crossing the isoelectric line and the end-point was referred as the end of the deflection crossing the isoelectric line. P wave duration was measured from the onset to the offset of the P wave. The patients were excluded if these points were not clear. Maximum P wave duration is defined as the longest P wave duration and minimum P wave duration is defined as the shortest P wave duration. P wave dispersion defined as difference between maximum P wave duration and minimum P wave duration was also calculated. All the measurements were repeated three times and average values were accepted for each of electrocardiographic parameters. All of the measurements were performed by two experienced investigators unaware of the subject’s clinical status. The study was approved by the local ethics committee of our institution, and all patients gave written informed consent.
The SPSS statistical software package (version 11.0) was used to perform all statistical calculations. Continuous variables were expressed as mean values ± SD, and categorical variables as percentages. Pearson correlations were used to compare associations between indexes. Categorical variables were compared by Pearson chi-square test. Comparisons of continuous variables between two groups have been performed by means of unpaired Student’s t test. For all tests, a value of P < 0.05 was considered statistically significant.
Table 1 The demographic and clinical characteristics of the RA patients and control subjects
Data are means ± SD, unless otherwise indicated BP blood pressure; ESR erythrocyte sedimentation rate, CRP C-reactive protein
Female:male Age (years) Body mass index (kg/m2) Heart rate (beat/min) Systolic BP (mmHg) Diastolic BP (mmHg) Disease duration (years) Morning stiffness duration (min) Tender joint count Swollen joint count Patient global assessment Disease activity score (DAS 28) Moderate activity (n, %) High activity (n, %) HAQ score Steinbrocker’s criteria (n, %) I II III ESR (mm/h) CRP (mg/dl)
Results The demographic and clinical characteristics of the RA patients and the controls were shown in Table 1. There was no significant difference between the two groups with regard to gender, age, body mass index (BMI), heart rate or blood pressure. In RA patients, the mean disease duration was 9.3 ± 8.7 years (range 1–40). All patients were treated with disease-modifying antirheumatismal drugs (methotrexate, sulphasalazine, leflunomide) and steroid. Electrocardiographic measurements and Doppler echocardiographic variables were shown in Table 2. Left atrial dimension, posterior wall thickening and left ventricular mass were significantly higher in RA patients than those of controls. However, there was no statistically significant difference between RA patients
RA patients (n = 30)
Control group (n = 27)
P value
28:2 49 ± 10 28 ± 5 77 ± 7 124 ± 13 77 ± 8 9.3 ± 8.7 28 ± 17 10.8 ± 3.7 4.8 ± 2.4 40.7 ± 11.8 5.4 ± 0.6 9 (30) 21 (70) 2.6 ± 1.1
24:3 47 ± 8 28 ± 4 74 ± 5 118 ± 13 76 ± 9 – – –
0.762 0.090 0.894 0.079 0.116 0.616
8 (27) 18 (60) 4 (13) 38 ± 16 1.7 ± 1.8
–
11 ± 8 0.423 ± 0.66
0.006 0.001
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Table 2 Electrocardiographic and echocardiographic measurements of the RA patients and controls
Minimum P wave duration (ms) Maximum P wave duration (ms) P wave dispersion (ms) Aortic dimension (cm) Left atrial dimension (cm) Septal thickening (cm) Posterior wall thickening (cm) Left ventricle mass (g) Ejection fraction (%) Mitral E wave velocity (m/s) Mitral A wave velocity (m/s) Mitral E/A ratio Mit Edec (ms) IVRT (ms)
Control group (n = 27)
RA patients (n = 30)
P value
72 104 31 2.7 2.8 0.9 0.8 163 69 0.77 0.70 1.1 0.81 107
67 110 42 2.8 3.1 1.0 0.9 197 69 0.72 0.81 0.9 0.77 114
0.152 0.031 0.001 0.326 0.016 0.270 0.013 0.045 0.820 0.210 0.022 0.011 0.695 0.088
± ± ± ± ± ± ± ± ± ± ± ± ± ±
10 10 9 0.2 0.3 0.1 0.1 67 5 0.17 0.17 0.4 0.34 16
± ± ± ± ± ± ± ± ± ± ± ± ± ±
12 8 12 0.3 0.4 0.2 0.1 53 6 0.14 0.18 0.2 0.45 15
Data are means ± SD, unless otherwise indicated IVRT isovolumetric relaxation time
and controls in other echocardiographic variables (Table 2). Among the pulse-wave Doppler indices of left ventricular diastolic function, compared with the control group, mitral A wave velocity was significantly higher in RA patients compared to healthy controls. Mitral E/A ratio was significantly lower in RA patients (Table 2). Maximum P wave duration and P wave dispersion were significantly higher in RA patients than those of controls. However, there was no significant difference in minimum P wave duration between two groups (Table 2). P wave dispersion was significantly correlated with only disease duration (r = 0.375, P = 0.009) and IVRT (r = 0.390, P = 0.006). However, there was no statistically significant correlation between P wave dispersion and other clinical and echocardiographic parameters (Table 3). In addition, there was no significant correlation between disease activity (DAS 28) and maximum, minimum P wave duration and P wave dispersion (r = –0.066, P = 0.743; r = –0.201, P = 0.316; r = 0.137, P = 0.497, respectively).
Discussion Cardiovascular involvement is one of the most important complications of RA and may contribute significantly to mortality. Fifty percent of deaths are due to cardiovascular diseases in RA [13]. However, many of RA patients did not experience clinical cardiac symptoms [14]. Cardiac disease is often clinically silent in patients with RA. In the previous studies, it has been reported that QT dispersion, which is a
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Table 3 The results of correlation analysis between P wave dispersion and clinical and echocardiographic parameters P wave dispersion
Aortic dimension Left atrial dimension Septal thickening Posterior wall thickening Left ventricle mass Ejection fraction Mitral E wave velocity Mitral A wave velocity Mitral E/A ratio Mit Edec IVRT Disease duration Morning stiffness duration Disease activity score (DAS 28) HAQ score ESR (mm/h) CRP (mg/dl)
r
P value
–0.170 0.056 0.102 0.198 0.169 0.131 –0.212 0.022 –0.189 0.192 0.390 0.375 0.107 0.137 0.165 0.130 0.038
0.253 0.707 0.498 0.187 0.257 0.312 0.149 0.884 0.209 0.192 0.006 0.009 0.595 0.497 0.411 0.553 0.856
predictor of ventricular arrhythmias, increased in patients with RA [15, 16]. In several studies, relationship between QT dispersion and disease duration was evaluated [15–17]. This matter is unclear. However, Cindas et al. [15] found that QT dispersion was associated with disease duration in patients with RA. We hypothesized that QT dispersion may be not only affected in patients with RA but also P wave dispersion may be affected. Therefore, we investigated P wave dispersion in patients with RA. P wave dispersion is a new electrocardiographic marker that has been associated with the heterogeneous and discontinuous propagation of sinus impulses. Furthermore, the correlation between the presence of intra-atrial
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conduction abnormalities and the induction of paroxysmal AF has been well documented [6–8, 18, 19]. Prolonged P wave duration and increased PWD have been reported to carry an increased risk for atrial fibrillation [6–8, 20]. Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk of AF [6–8]. To our knowledge, no previous studies have compared P wave duration and PWD of RA patients to healthy controls. Our study is the first that has investigated the P wave duration and PWD changes in RA patients. This study shows that maximum P wave duration and PWD are higher in RA patients than control subjects. These results suggest that RA patients may be under the risk for atrial fibrillation. This study also shows that PWD was correlated with disease duration and IVRT which is a parameter of left ventricular diastolic dysfunction. It has been reported that P wave dispersion was associated with diastolic dysfunction, LAD and coronary artery disease [21–23]. We found that P wave dispersion was associated with diastolic dysfunction. Although LAD was significantly higher in RA patients than controls, there was no correlation between P wave dispersion and LAD. This result may be caused by small study population. The precise mechanism of arrhythmias seen in RA is not clear. Sudden deaths can be due to arrhythmias caused by myocardial inflammation or rheumatoid nodules [24]. Coronary atherosclerotic disease and coronary vasculitis were reported in patients with RA [24–26]. Arrhythmias and conduction defects were seen due to vasculitis and myocardial involvement in the vessels perfusing atrioventricular node and conducting bundles [13]. It has also been reported that disease-modifying antirheumatic drugs used by RA patients may cause repolarization abnormalities [27–29]. For instance, Chloroquine has cardiotoxic side effects [27, 28]. Gold salts and D-penicillamine are known to be capable of causing vasculitis, which may lead to myocardial dysfunction [29]. Sulfasalazine, methotrexate, leflunomid, nonsteroidal antiinflammatory drugs and steroids have known no direct cardiotoxic side effects [30–34]. Our patients were treated with sulphasalazine, methotrexate and leflunomide following the diagnosis of RA. None were treated with gold salts or D-penicillamine. In addition, Tukek et al. suggested that increased sympathetic activity may cause significant increase in PWD [35]. Some studies have shown that sympathetic nervous system activity was increased in patients with RA [36, 37]. P wave dispersion may be associated with increased sympathetic nervous system activity in patients with RA.
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This study population is relatively small and therefore our results should not be extrapolated to all RA patients. CAD cannot be precisely externalized because coronary angiography, which is an invasive method, was not performed on patients and control subjects. Other studies and the results of present study suggested that RA patients may be under the risk for both ventricular and atrial arrhythmias. However, it has been reported that there was no difference in rhythm disorders between RA patients and controls who were observed with 24 h Holter monitoring [2]. Therefore, further studies are necessary to investigate the frequency of atrial arrhythmias by rhythm holter in patients with RA, who have or do not have high P wave dispersion. Consequently, involvement of the heart may be seen in RA patients even in the absence of clinical cardiac manifestations. In this study, P wave duration and P wave dispersion was found to be higher in RA patients than healthy control subjects. PWD was found to be associated with disease duration and diastolic dysfunction. Therefore, the patients with RA who have increased PWD should be closely followed for atrial arrthythmias.
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