Effect of Ongoing Inflammation in Rheumatoid Arthritis on P-Wave Dispersion

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1 The Journal of International Medical Research 2007; 35: Effect of Ongoing Inflammation in Rheumatoid Arthritis on P-Wave Dispersion M YAVUZKIR 1, A OZTURK 2, N DAGLI 1, S KOCA 2, I KARACA 1, M BALIN 1 AND A IşIK 2 1 Department of Cardiology, and 2 Department of Rheumatology, Firat University, School of Medicine, Elazig, Turkey It has been emphasized recently that there is a strong association between atrial fibrillation and inflammation. Rheumatoid arthritis (RA), characterized by ongoing inflammatory activity, can increase the risk of atrial arrhythmia. P-wave dispersion has been encountered as a risk factor for atrial fibrillation and the effect of inflammation on P-wave dispersion has not been studied thoroughly. The aim of this study was to examine the effect of ongoing inflammatory activity in RA on P-wave dispersion. The study comprised 82 patients diagnosed with RA and 41 healthy volunteers as controls. Systolic functions of all participants were evaluated by echocardiography. Maximum P-wave duration and dispersion were calculated and found to be significantly increased in the RA group compared with the healthy controls. These parameters were also significantly correlated with C-reactive protein levels. The findings of this study suggest that RA may be associated with increases in P-wave dispersion and maximum P-wave duration, and that this association may result from ongoing inflammation. KEY WORDS: RHEUMATOID ARTHRITIS; INFLAMMATION; P-WAVE DISPERSION; P-WAVE DURATION; C-REACTIVE PROTEIN Introduction Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown aetiology that affects 1% of the general adult population. 1,2 Patients with RA not only have a higher chronic disease burden compared with healthy subjects, 3,4 but may also have increased morbidity and mortality from cardiovascular disease. 2,5 7 There is a consistent and significant association (in all populations who have inflammatory diseases such as RA, systemic lupus erythematosus or high C-reactive protein [CRP] levels) between inflammation and risk of future cardiovascular events (stroke, peripheral vascular disease, sudden cardiac death, arrhythmia, plaque rupture and recurrent ischaemia, and myocardial infarction) Although the cause of atrial fibrillation is unknown, evidence from both laboratory and epidemiological research suggests that systemic inflammation can play a role. 11 Rheumatoid arthritis, characterized by increased inflammatory activity, 12 may enhance the risk of atrial arrhythmia. 796

2 Maximum P-wave duration (P max ) and P-wave dispersion (PD), defined as P max P min (minimum P-wave duration), on a standard electrocardiogram (ECG) are noninvasive markers of inhomogeneous and discontinuous propagation of sinus impulses through the atrial wall that are believed to be one of the electrophysiological causes of atrial fibrillation. 13,14 To the best of our knowledge, the effect of inflammation on PD has not been comprehensively analysed in patients with RA. The aim of the present study was, therefore, to examine the effects of RA on PD. Patients and methods PATIENTS The study included patients who were diagnosed as having RA according to the diagnostic criteria of the American College of Rheumatology 15 and a control group of healthy volunteers. The study was approved by the Firat University School of Medicine Ethics Committee in accordance with the Declaration of Helsinki. All participants were informed about the study and their written informed consent forms were obtained. Exclusion criteria were: coronary artery disease, systolic heart failure (ejection fraction < 45%), hypertension, diabetes mellitus, arrhythmia, pacemaker rhythm, anti-arrhythmic treatment (amiodarone, β-blockers, calcium channel blockers, etc.), obesity (body mass index [BMI] > 35 kg/m 2 ), valve disease, pulmonary hypertension, chronic obstructive lung disease, neurological disease, pregnancy, an echocardiographic image that was technically insufficient, QRS duration > 120 ms, low P amplitude, end of the P-wave could not be discerned, and the pulsus paradoxus measurement could not be performed by at least nine derivations on ECG. STUDY DESIGN Histories on all the participants were collected and a routine physical examination was performed. The BMI and body surface area were calculated by measuring weight and height. The duration of RA was recorded. Blood samples were collected between and 09.00, after h of fasting and sera were separated by centrifugation at 1500 g for 10 min. Routine biochemical parameters were evaluated in serum samples with an Olympus AU 600 autoanalyzer using Olympus kits (Olympus Corp., Tokyo, Japan). Haematological parameters were measured using Advia 120 (Hematology Systems, Bayer, Leverkusen, Germany). Erythrocyte sedimentation rate (ESR) was determined immediately by the Westergren method in whole blood with 1 mg/ml ethylenediaminetetraacetic acid. CRP levels and rheumatoid factor titres were determined by the immunoturbidimetric technique (Schiapparelli Biosystems, Woerden, The Netherlands) and nephelometric method (BN II; Dade Behring, Marburg, Germany), respectively. ELECTROCARDIOGRAPHY A 12-lead surface ECG was obtained from all subjects in the supine position using an electrocardiograph (Nihon Kohden Corp., Tokyo, Japan). All patients were breathing freely but were not allowed to speak during the ECG recordings. The ECG was recorded at a paper speed of 50 mm/s and 12 leads were recorded simultaneously. P-wave duration was measured manually using a 10- magnifying lens in all derivations. The beginning of the P wave was taken as the point at which the isoelectric line and P wave intersected. The P max was taken as the longest P wave (the longest atrial conduction time). The difference P max P min was regarded as PD. 13 The measurements were 797

3 evaluated separately and single-blindly by two cardiologists who were unaware of the clinical characteristics of the patients. The arithmetic mean of two values obtained by the investigators for each ECG variable in each patient was used for further statistical analysis to determine the intra- and interobserver error margins. ECHOCARDIOGRAPHY Echocardiographic examination was performed for all study subjects using a commercially available system (Acuson Sequoia 512, Mountain View, CA, USA) with a 3 MHz transducer. M-mode echocardiographic measurements were obtained according to the standards of the American Society of Echocardiography. 16 Left atrial diameter, left ventricular end-systolic and end-diastolic diameters, end-diastolic interventricular septal thickness and enddiastolic left ventricular posterior wall thickness were measured and left ventricular ejection fraction was determined. STATISTICAL ANALYSIS Statistical evaluation of the data was carried out using the Statistical Package for Social Sciences (SPSS version 11.0; SPSS Inc., Chicago, IL, USA). General definitive characteristics were evaluated as mean ± SD. The χ 2 test was used to compare sex and risk factors between the groups. Significant differences for the two groups were evaluated by Student s t-test. The Mann Whitney U-test was used for comparison of inflammation parameters (C-reactive protein, rheumatoid factor, ESR and white blood cell count) between the groups. Correlations of P max and PD with CRP were evaluated by the Pearson correlation test. P-values < 0.05 were considered to be statistically significant. Results The study included 82 RA patients (69 females and 13 males, with a mean age of 52.3 ± 11.8 years, and a mean disease length of 6.8 ± 7.3 years [range 1 30 years]) who were diagnosed according to the diagnostic Time (ms) RA P < P < Healthy PD P max FIGURE 1: Comparison of the maximum P-wave duration (P max ) and P-wave dispersion (PD) between rheumatoid arthritis (RA) patients (n = 82) and the healthy control group (n = 41). The top and bottom of the boxes show the SDs and the upper and lower whisker bars show the highest and lowest recorded measurements, respectively. 798

4 criteria of the American College of Rheumatology. 15 The control group comprised 41 healthy volunteers (32 females and nine males, with a mean age of 49.8 ± 11.1 years [range years]). Demographical parameters were not significantly different (P > 0.05). Of the 82 patients in the RA group, 40 were using a combination of methotrexate, sulfasalazine, chloroquine and corticosteroid. The remaining 42 patients were receiving corticosteroid in addition to one of the basic drugs like methotrexate, sulfasalazine and lenflunomide. The inter- and intraobserver variability for the ECG measurements were 3 ± 4% and 1 ± 3%, respectively. There was a significant difference in PD between the RA group (55.6 ± 7.5 ms) and the healthy control group (42.2 ± 7.5 ms) (P < 0.001). The P max was found to be significantly increased in the RA group (92.9 ± 13.1 ms) compared with the healthy control group (76.3 ± 9.6 ms) (P < 0.001, Fig. 1, Table 1). No significant differences were observed between the two groups for pulse, blood pressure, ejection fraction and left atrial diameter (Table 1). The ESR, white blood cell count and rheumatoid factor levels in the RA patients were significantly higher than those in the healthy control group (P < 0.001; Table 1). The P max and PD values significantly correlated with C-reactive protein levels (r = 0.32, P < 0.05 and r = 0.36, P < 0.05, respectively). Discussion The major findings of this study are: (i) patients with RA had a significantly higher P max and PD compared with healthy subjects; (ii) inflammatory markers in the RA patients were seen to be markedly higher than in the healthy subjects; and (iii) PD correlated with CRP. Rheumatoid arthritis is a chronic inflammatory disease that progresses with TABLE 1: Electrocardiographic, M-mode echocardiographic and inflammatory marker data of the study participants Rheumatoid arthritis Healthy control group a group Parameter (n = 82) (n = 41) P-value Pulse (beats/min) 82.3 ± ± 9.5 NS Systolic blood pressure (mmhg) ± ± 23.4 NS Diastolic blood pressure (mmhg) 86.3 ± ± 19.6 NS Maximum P-wave duration (ms) 92.9 ± ± 9.6 < P-wave dispersion (ms) 55.6 ± ± 7.5 < Ejection fraction (%) 61.1 ± ± 6.1 NS Left atrial diameter (mm) 35.3 ± ± 2.9 NS Rheumatoid factor (IU/Ml) ± ± 13.4 < C-reactive protein (mg/dl) 35.3 ± ± 10.1 < Erythrocyte sedimentation rate (mm/h) 42.5 ± ± 10.4 < White blood cell count (10 3 /µl) ± ± < Values are mean ± SD. a Rheumatoid arthritis was diagnosed according to the diagnostic criteria of the American College of Rheumatology. 15 NS, not significant. 799

5 acute aggravations. 1 4 It has been shown in many studies that cytokines and acute phase markers are increased and that inflammation is chronic in RA. 12 Of the inflammatory markers, CRP is synthesized by the liver in response to interleukin-1, interleukin-6 and other cytokines. 17 Increased CRP levels show both the activity of this chronic disease and make up an independent risk factor for atherosclerosis 8,18 and arrhythmias. 19 Elevated ESR and leucocytes are expected findings in this chronic inflammatory process and were shown in previous studies to be associated with cardiovascular events. 8,18,20 Even antitumour necrosis factor drugs, which are the most effective, have been shown to provide a remission rate of only 50% in RA, 21 and CRP levels, although reduced, could not be restored to normal. 22 Although our RA cases received treatment, inflammatory markers such as CRP and ESR were significantly higher than in the healthy controls. This ongoing inflammation might affect the myocardium; increased inflammatory activity is almost always associated with poor cardiac prognosis. The P max and PD comprise noninvasive markers that show heterogeneous and discontinuous propagation originating from the sinus node on the atrium wall. 13 Elevated heterogeneous and discontinuous propagation of electrical activity in the atrial myocardium causes a different conduction rate and atrial re-entry, due to the shortening of the refractory period. Atrial reentry is an electrophysiological mechanism that plays an important role in the development of atrial fibrillation. A possible mechanism for the increased PD found on ECG examination of the RA cases in the present study may be as follows. Elevated inflammatory markers in circulation, like CRP, bind to ligands in the atrial myocardium and activate the complement system in RA. 23 Local atrial complement activation then leads to tissue injury in the atrial myocardium, 24 and myocyte necrosis and fibrosis result in atrial remodelling. This may directly cause a fluctuation in the membrane potentials of atrial myocytes and interstices. 25 These structural changes, occurring within the atrial wall, might lead to electrical inhomogeneity, disparate conduction velocities and inhomogeneous refractory periods throughout the atrial myocardium, which might reflect on ECG examination as prolonged P-wave duration and increased PD. It was emphasized recently that there was a close association between atrial fibrillation and inflammation; atrial fibrillation was found to be more common in cases that had high CRP levels following coronary bypass, 23 cardioversion 26 and acute pericarditis. 27 There was a correlation between CRP and PD in our RA patients and this indicates that inflammation might play an important role in the pathogenesis of atrial arrhythmias. Measurement of PD is highly important. It has been reported that making an ECG record at 50 mm/s paper speed facilitates PD measurement 13,14 and, in our study, we took ECG measurements at that speed. Intra- and interobserver error margin should be determined for these measurements and, therefore, we calculated error margins for each ECG for each patient by taking the mean of the two values calculated by two independent researchers who were blind to the clinical data. Interobserver variability was 3 ± 4% and intraobserver variability was 1 ± 3%. It has been reported that P max and PD are associated with age, 28 left ventricular systolic function, 29 left atrium size 30 and increased sympathetic activity. 31 In our study there was 800

6 no significant difference between the two groups in terms of these measures. The present study had a number of limitations, the main one being the small population size. Another limitation was that the ECG measurements were performed manually using a 10 magnifying lens without the use of a computer program. The patients were also not subjected to an electrophysiological evaluation. In addition, atrial pressure and pulmonary wedge pressures were not measured by an invasive method and only a limited number of inflammatory markers (ESR, CRP, rheumatoid factor) were studied. Cytokine levels and disease activity criteria were not determined and patients were not followed up in terms of long-term mortality and morbidity. In conclusion, the present study showed that PD and P max increased on surface ECG measurement in RA patients. These results may indicate that ongoing inflammation in RA might cause inhomogeneous and discontinuous propagation of sinus impulses through the atrial wall. Conflicts of interest No conflicts of interest were declared in relation to this article. Received for publication 23 May 2007 Accepted subject to revision 6 June 2007 Revised accepted 21 September 2007 Copyright 2007 Field House Publishing LLP References 1 Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998; 41: Gabriel SE: The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 2001; 27: Gabriel SE, Crowson CS, O Fallon WM: Comorbidity in arthritis. J Rheumatol 1999; 26: Mikuls TR, Saag KG: Comorbidity in rheumatoid arthritis. Rheum Dis Clin North Am 2001; 27: Bacon PA, Townend JN: Nails in the coffin: increasing evidence for the role of rheumatic disease in the cardiovascular mortality of rheumatoid arthritis [editorial]. Arthritis Rheum 2001; 44: Vandenbroucke JP, Hazevoet HM, Cats A: Survival and cause of death in rheumatoid arthritis: a 25-year prospective followup. J Rheumatol 1984; 11: Mutru O, Laakso M, Isomaki H, et al: Cardiovascular mortality in patients with rheumatoid arthritis. Cardiology 1989; 76: Danesh J, Whincup P, Walker M, et al: Low grade inflammation and coronary heart disease: prospective study and updated metaanalyses. BMJ 2000; 321: Szmitko PE, Wang CH, Weisel RD, et al: New markers of inflammation and endothelial cell activation: Part I. Circulation 2003; 108: Rost NS, Wolf PA, Kase CS, et al: Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001; 32: Boos CJ, Anderson RA, and Lip GY: Is atrial fibrillation an inflammatory disorder? Eur Heart J 2006; 27: Kirwan JR: Links between radiological change, disability, and pathology in rheumatoid arthritis. J Rheumatol 2001; 28: Dilaveris PE, Gialafos EJ, Sideris SK, et al: Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation. Am Heart J 1998; 135: Dilaveris PE, Gialafos EJ, Andrikopoulos GK, et al: Clinical and electrocardiographic predictors of recurrent atrial fibrillation. Pacing Clin Electrophysiol 2000; 23: Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: Rogers EW, Feigenbaum H, Weyman AE: Echocardiography for quantification of cardiac chambers. In: Progress in Cardiology (Yu PN, Goodwin JF, eds). Philadelphia: Lea & Febiger, 1979; pp Mackiewicz A, Speroff T, Ganapathi MK, et al: Effects of cytokine combinations on acute 801

7 phase protein production in two human hepatoma cell lines. J Immunol 1991; 146: Ridker PM: Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: Chung MK, Martin DO, Sprecher D, et al: C- reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001; 104: Madjid M, Awan I, Willerson JT, et al: Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol 2004; 44: van der Bijl AE, Allaart CF, Van Vugt J, et al: Rheumatoid vasculitis treated with infiximab. J Rheumatol 2005; 32: Quinn MA, Conaghan PG, O Connor PJ, et al: Very early treatment with infliximab in addition to methotrexate in early, poorprognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005; 52: Bruins P, te Velthuis H, Yazdanbakhsh AP, et al: Activation of the complement system during and after cardiopulmonary bypass surgery. Post-surgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 1997; 96: Marnell L, Mold C, Du Clos TW: C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005; 117: Klein RM, Vester EG, Brehm MU, et al: Inflammation of the myocardium as an arrhythmia trigger. Z Kardiol 2000; 89 (suppl 3): Malouf JF, Kanagala R, Al Atawi FO, et al: High sensitivity C-reactive protein: a novel predictor for recurrence of atrial fibrillation after successful cardioversion. J Am Coll Cardiol 2005; 46: Spodick DH: Arrhythmias during acute pericarditis. A prospective study of 100 consecutive cases. JAMA 1976; 235: Turhan H, Yetkin E, Sahin O, et al: Comparison of P-wave duration and dispersion in patients aged 65 years with those aged 45 years. J Electrocardiol 2003; 36: Senen K, Turhan H, Riza Erbay A, et al: P-wave duration and P-wave dispersion in patients with dilated cardiomyopathy. Eur J Heart Fail 2004; 6: Tukek T, Akkaya V, Atilgan D, et al: Effect of left atrial size and function on P-wave dispersion: a study in patients with paroxysmal atrial fibrillation. Clin Cardiol 2001; 24: Tukek T, Akkaya V, Demirel S, et al: Effect of Valsalva maneuver on surface electrocardiographic P-wave dispersion in paroxysmal atrial fibrillation. Am J Cardiol 2000; 85: Author s address for correspondence Dr Mustafa Yavuzkir Firat (Euphrates) Üniversitesi, Firat Tip Merkezi, Kardiyoloji Anabilim Dali, Elazig, Turkey. mfyavuzkir@firat.edu.tr 802