The Role of Inflammation in Atrial Fibrillation following Open Heart Surgery

The Journal of International Medical Research 2008; 36: 1070 1076 The Role of Inflammation in Atrial Fibrillation following Open Heart Surgery S CANBAZ 1, H ERBAS 2, S HUSEYIN 1 AND E DURAN 2 1 Department of Cardiovascular Surgery, and 2 Department of Biochemistry, Medical Faculty, Trakya University, Edirne, Turkey This study investigated the role of systemic inflammation in the development of atrial fibrillation (AF) after coronary artery bypass grafting (CABG). CABG was performed using cardiopulmonary bypass in 77 patients. Pre-operative AF was present in six patients (7.8%) and postoperative AF developed in 13 (18.3%) of the 71 patients with pre-operative sinus rhythm. Post-operative mediastinal drainage was significantly increased in patients with post-operative AF compared with those with sinus rhythm. Plasma E- selectin, P-selectin and vascular cell adhesion molecule levels were not significantly different between patients with pre- and post-operative sinus rhythm, those with pre-operative sinus rhythm and post-operative AF, and those with pre- and post-operative AF. There were significant differences between preand post-operative C-reactive protein, interleukin (IL)-6 and IL-10 levels within all three groups, but no differences in these parameters between the groups. Thus, in all groups there were significant alterations in mediators indicative of systemic inflammation following CABG, but comparisons between the groups revealed no differences predictive of AF. KEY WORDS: ATRIAL FIBRILLATION; CORONARY ARTERY BYPASS GRAFTING; CARDIOPULMONARY BYPASS; INFLAMMATION; E-SELECTIN; P-SELECTIN; C-REACTIVE PROTEIN; VASCULAR CELL ADHESION MOLECULE; INTERLEUKIN-6; INTERLEUKIN-10 Introduction Following open heart surgery, coronary artery bypass grafting (CABG) and valvular surgery, cardiac rhythm disturbances such as atrial fibrillation (AF) occur in 20 40% of patients. 1 3 Such complications extend the length of hospital stay required and the medications and treatment needed increase the costs. Atrial thrombi are frequently formed in cases of AF and those that break off from the atrium can cause acute occlusion of various arteries, especially when the cardiac rhythm is altered. Thus, AF is associated with an increase both in morbidity and mortality. Atrial fibrillation frequently develops on the second or third post-operative days. 4,5 Although it has been investigated in many studies, the precise aetiology of AF has not yet been established. Suggested aetiological factors include advanced age, excessive postoperative mediastinal bleeding, severity of coronary disease, atrial ischaemia, preoperative β-blocker usage, chronic obstructive pulmonary disease (COPD) and renal failure. 1 9 In addition, cardiac, pericardial and mediastinal inflammation has been implicated in post-operative AF following 1070

cardiopulmonary bypass (CPB). 6,10,11 It is well known that there is an increase in systemic inflammation during and after open heart surgery when CPB is used. 1,6 Preliminary studies have indicated that this is associated with changes in plasma levels of several adhesion molecules and selectins. 10 15 Various adhesion molecules, selectins and cytokines, including E-selectin, P-selectin, interleukin (IL)-6, IL-10, vascular cell adhesion molecule (VCAM) and C- reactive protein (CRP), are strong indicators of systemic inflammation. The purpose of this study was, therefore, to investigate the role of increased inflammation in the aetiology of post-operative AF by measuring the plasma levels of these endogenous agents and cytokines before and on the third day after CABG. Patients and methods PATIENTS Consecutive CABG patients from the Department of Cardiovascular Surgery, Medical Faculty, Trakya University were enrolled in this prospective study. Patients were excluded if they underwent procedures in addition to CABG and valve surgery, such as beating heart surgery, or if they had liver or kidney failure, emergency status or a European System for Cardiac Operative Risk Evaluation (EuroSCORE) of 6. 16 For the purposes of analysis, patients were divided into three groups: those with pre- and postoperative sinus rhythm (sinus rhythm group); those with pre-operative sinus rhythm and post-operative AF (postoperative AF group); and those with pre- and post-operative AF (AF group). All patients gave written informed consent. The study protocol was designed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Trakya University. TREATMENT AND EVALUATION In addition to routine pre-operative evaluation, echocardiography was performed on all patients. All patients received cold cardioplegic solution with K + antegrade during hypothermic CPB. Surgery involved diverting the left internal mammary artery to form a bypass graft to the left anterior descending artery and/or using saphenous vein grafts for anastomoses to other coronary vessels. Post-operatively, patients who had no complications were cared for in the intensive care unit (ICU) for 2 days. Criteria for discharge from the ICU to the ward included withdrawal of all vasoactive and inotropic infusions, extubation without pulmonary support, and no evidence of major organ failure. Whilst in the ICU, patients were monitored using a six-channel, five-lead standard D-II derivation electrocardiogram (ECG). Pulse rate, arterial tension and body temperature were assessed every 2 h for the first 2 days in the ward and subsequently every 4 h. Every morning, a 12-lead ECG was performed in both the ICU and the ward. If arrhythmia was suspected, a standard ECG was also performed. Routine amiodarone treatment was administered to patients with AF. This comprised an initial 2 h amiodarone infusion (300 mg in 5% dextrose solution) and then a maintenance dose for 3 days (450 mg/day infusion [total dose 1350 mg]), followed by oral amiodarone. The oral dose was tapered as follows: 1200 mg oral amiodarone for the first 3 days; 600 mg for the next 2 weeks; and 200 mg for the next 3 months. All patients received several doses of β-blockers pre-operatively, and acetylsalicylic acid and β-blockers were given on the first post-operative day. Age, gender, body surface area, the presence of diabetes, hypertension, COPD or pre-operative arrhythmia, ejection fraction, 1071

drug usage, number of arterial grafts performed, CPB time, aortic cross-clamp time, post-operative mediastinal drainage, and the number of days in the ICU were recorded for each patient. MEASUREMENT OF SYSTEMIC INFLAMMATION Blood samples were taken 1 day before the operation and on the third post-operative day; specimens were immediately placed in glass tubes without anticoagulants or preservatives. The serum was separated by centrifugation, placed in plastic tubes and frozen at 80 C until analysed. Concentrations of E-selectin, P-selectin, IL-6, IL-10, VCAM and CRP were measured using standard enzyme-linked immunosorbent assays. STATISTICAL ANALYSIS All results were analysed by SPSS software (SPSS Inc., Chicago, IL, USA) using the Wilcoxon signed-rank test. A P-value < 0.05 was considered to be statistically significant. Results A total of 77 consecutive CABG patients were enrolled into the study. Of these, 58 (75.3%) had pre- and post-operative sinus rhythm, 13 (16.9%) had pre-operative sinus rhythm and post-operative AF, and six (7.8%) had pre-operative AF that continued into the post-operative period. Treatment with intravenous and oral amiodarone restored normal sinus rhythm in all 13 of the 71 patients (18.3%) who developed postoperative AF. Demographic and pre-operative data and operative parameters for each of the three groups of patients are given in Tables 1 and 2. There were no statistically significant differences between the groups in terms of age, gender, body surface area, presence of hypertension or COPD, β-blocker usage or left ventricular ejection fraction. With regards to operative parameters, there were no significant differences between the groups in the number of distal anastomoses, total CPB time or aortic cross-clamp time. There was, however, significantly more mediastinal drainage, indicating greater post-operative blood loss, in the postoperative AF group compared with the other two groups (P < 0.05). TABLE 1: Demographic and pre-operative characteristics of patients undergoing coronary artery bypass grafting Sinus rhythm Post-operative group AF group AF group (n = 58) (n = 13) (n = 6) Age (mean ± SD) (years) 57 ± 10 56 ± 9 63 ± 13 Gender (n) Male 46 11 4 Female 12 2 2 Body surface area (mean ± SD) (m 2 ) 1.8 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 Hypertension 41% 46% 50% COPD 8% 15% 16% β-blocker usage 100% 100% 100% Left ventricular ejection fraction (mean ± SD) 54 ± 11% 49 ± 8% 46 ± 9% COPD, chronic obstructive pulmonary disease. 1072

TABLE 2: Operative parameters in patients undergoing coronary artery bypass grafting Sinus rhythm Post-operative group AF group AF group (n = 58) (n = 13) (n = 6) Number of distal anastomoses 2.9 ± 0.9 3.2 ± 0.9 2.8 ± 0.7 Cardiopulmonary bypass time (min) 100 ± 43 96 ± 41 85 ± 14 Aortic cross-clamp time (min) 55 ± 19 63 ± 2 53 ± 6 Mediastinal drainage (ml) 723 ± 370 1180 ± 642* 698 ± 457 Values given are means ± SD. *P < 0.05 compared with the sinus rhythm and AF groups. Pre- and post-operative plasma levels of E- selectin, P-selectin, IL-6, IL-10, VCAM and CRP are shown in Table 3. Although the pre- and post-operative plasma E-selectin levels were not significantly different in the sinus rhythm and AF groups, the post-operative E-selectin level was significantly lower than the preoperative level in the post-operative AF group (P < 0.05). Pre- and post-operative plasma P- selectin levels did not differ significantly in any of the groups. Post-operative plasma IL-6 levels were, however, more than three-fold higher than pre-operative levels in all three groups (P < 0.05 P < 0.01). Similarly, plasma IL-10 levels were also significantly increased post-operatively in all three groups (P < 0.05 P < 0.01). Pre- and post-operative VCAM levels differed significantly in the sinus rhythm group, but not in the other two groups (P < 0.05). Post-operative CRP values were significantly higher than pre-operative levels in all three groups (P < 0.01). There were no significant differences in the levels of any of the above-mentioned parameters between the groups, apart from the pre-operative IL-10 level, which was significantly lower in the AF group than in the other two groups (P < 0.05). TABLE 3: Pre- (pre-op.) and post-operative (post-op.) plasma E-selectin, P-selectin, interleukin-6 (IL-6), interleukin-10 (IL-10), vascular cell adhesion molecule (VCAM) and C-reactive protein (CRP) levels in patients undergoing coronary artery bypass grafting Sinus rhythm group Post-operative AF group AF group (n = 58) (n = 13) (n = 6) Pre-op. Post-op. Pre-op. Post-op. Pre-op. Post-op. E-selectin (ng/ml) 70 ± 9 67 ± 7 119 ± 7* 62 ± 5 131 ± 162 58 ± 36 P-selectin (ng/ml) 82 ± 37 94 ± 5 74 ± 31 69 ± 30 90 ± 45 127 ± 30 IL-6 (pg/ml) 9 ± 11* 27 ± 37 11 ± 19* 38 ± 36 7 ± 3** 26 ± 7 IL-10 (ng/dl) 5 ± 8** 12 ± 15 6 ± 8** 19 ± 13 3 ± 1* 8 ± 6 VCAM (ng/ml) 797 ± 293* 924 ± 424 902 ± 320 1021 ± 351 1140 ± 414 1200 ± 783 CRP (mg/l) 17 ± 14** 45 ± 17 23 ± 17** 53 ± 17 16 ± 9** 47 ± 17 Values given are means ± SD. *P < 0.05 and **P < 0.01 compared with the post-operative value. P < 0.05 compared with the sinus rhythm group and the post-operative AF group. 1073

Discussion Post-operative AF is a frequent complication of cardiac operations. 1 5 It requires careful management in order to minimize problems such as a prolonged stay in the ICU, morbidity and resource consumption. Many prospective and retrospective studies suggest that several different risk factors affect the development of AF. 3 6,9 Advanced age, surgical trauma, mediastinal bleeding and the use of β-blocking agents are currently accepted as associated factors. In a retrospective study performed a few years ago, we found that patients with postoperative AF were older and had more postoperative mediastinal bleeding than sinus rhythm patients. 5 In the present study, despite the groups being age-matched, significantly more post-operative mediastinal drainage still occurred in patients with post-operative AF than in the other two groups. It is well known that CPB causes intensive complement activation and disseminated systemic inflammation during the postoperative period. 10,11 Endogenous cytokines have an essential role in this inflammatory response and CRP is a widely known marker of body inflammation that has been used for many years in the diagnosis of infection. An increase in CRP after cardiac surgery is well documented. 14 In the present study postoperative plasma CRP levels showed a statistically significant increase compared with pre-operative values in all three groups. This is important because it indicates that CPB is associated with significant inflammation. The increased CRP level occurred in all three groups, however differences between the groups were not significant. It has been shown that CRP increases in patients with paroxysmal AF; 12,13 however, in the present study, analysis of the CRP levels in the AF and sinus rhythm groups did not suggest an aetiology for the development of post-operative AF. In addition, no relationship was found between the development of AF and plasma CRP levels following open heart surgery in women. 14 E-selectin secretion from plasma endothelial cells and P-selectin secretion from thrombocytes have been frequently reported to be strong indicators of inflammation. 10,11,15,17 The marked alteration in plasma selectin level during CPB is similar to that observed in acute organ dysfunction, atherosclerosis, coronary artery disease, unstable angina pectoris and ischaemic stroke. 18 23 In the present study, the SD for measurement of E- and P-selectin varied widely and this may have contributed to no statistically significant differences between the pre- and post-operative plasma P-selectin levels being detected in any of the three groups, particularly as the mean postoperative P-selectin level in the AF group was quite a lot higher than the pre-operative level. Levels of post-operative plasma E- selectin decreased from pre-operative values, however a statistically significant reduction could be detected only in the post-operative AF group. The mean post-operative E- selectin level in the AF group was also quite a lot lower than the pre-operative level, though not statistically significant. Plasma VCAM is an important indicator of endothelial cell activation and vessel wall inflammation. 24 26 While there was a significant increase between the pre- and post-operative levels of VCAM in the sinus rhythm group in the present study, this was not seen in the other groups and there were no differences between the groups. This suggests that there is no relationship between the development of AF and plasma VCAM level. Perhaps the most important findings of the present study were the changes in 1074

plasma IL-6 and IL-10 levels, which significantly increased post-operatively in all groups. This indicates that a disseminated systemic inflammatory response develops in all patients who have undergone open heart surgery, independently of AF. A rapid increase in IL levels early in the postoperative period with a decrease later has previously been reported. 27 In the present study the blood samples were obtained on the third post-operative day, but it is reasonable to suppose that the IL levels were also elevated earlier than this postoperatively. In summary, the present study showed that various pro-inflammatory products, plasma acute phase reactants, inflammatory cytokines and end-products of the vascular inflammatory response were changed following CPB and open heart surgery, which is consistent with the literature. These changes, however, were found not to be related to the presence of AF and we therefore conclude that these markers are not useful indicators of AF development. Post-operative disseminated systemic inflammation was seen in all patients, so the extent to which inflammation has a role in the development of AF following CABG cannot be determined and further investigation is required. Nevertheless, this prospective controlled clinical study is an important step in researching the role of inflammation in the aetiology of AF following CABG. Acknowledgement This study was supported by the Trakya University Research Fund (TUBAP-515; S Canbaz principal investigator). Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 13 April 2008 Accepted subject to revision 16 April 2008 Revised accepted 7 August 2008 Copyright 2008 Field House Publishing LLP References 1 Hogue CW Jr, Hyder ML: Atrial fibrillation after cardiac operation: risks, mechanisms, and treatment. Ann Thorac Surg 2000; 69: 300 306. 2 Ducceschi V, D Andrea A, Liccardo B, et al: Perioperative clinical predictors of atrial fibrillation occurrence following coronary artery surgery. Eur J Cardiothorac Surg 1999; 16: 435 439. 3 Waldo AL: Atrial fibrillation following open heart surgery: mechanism and treatment. In: Atrial Fibrillation: Mechanism and Therapeutic Strategies (Olsson SB, Allessia MA, Campbell RWF, eds). New York: Future Publishing Company, 1994; p 211 223. 4 Maisel WH, Rawn JD, Stevenson WG: Atrial fibrillation after cardiac surgery. Ann Intern Med 2001; 135: 1061 1073. 5 Canbaz S, Ege T, Sunar H, et al: Predictors of atrial fibrillation after coronary artery surgery: a retrospective study. Turkish J Thorac Cardiovasc Surg 2000; 8: 767 770. 6 Czerny M, Baumer H, Kilo J, et al: Inflammatory response and myocardial injury following coronary artery bypass grafting with or without cardiopulmonary bypass. Eur J Cardiothorac Surg 2000; 17: 737 742. 7 Chung MK: Cardiac surgery: postoperative arrhythmias. Crit Care Med 2000; 28: 136 144. 8 Kalman JM, Munawar M, Howes LG, et al: Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation. Ann Thorac Surg 1995; 60: 1709 1715. 9 Kuralay E, Ozal E, Demirkili U, et al: Effect of posterior pericardiotomy on postoperative supraventricular arrhythmias and late pericardial effusion (posterior pericardiotomy). J Thorac Cardiovasc Surg 1999; 118: 492 495. 10 Asimakopoulos G, Taylor KM: Effects of cardiopulmonary bypass on leukocyte and endothelial adhesion molecules. Ann Thorac Surg 1998; 66: 2135 2144. 11 Toft P, Christiansen K, Tønnesen E, et al: Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery. Scand Cardiovasc J 1997; 31: 283 288. 1075

12 Dernellis J, Panaretou M: C-reactive protein and paroxysmal atrial fibrillation: evidence of the implication of an inflammatory process in paroxysmal atrial fibrillation. Acta Cardiol 2001; 56: 375 380. 13 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: 2886 2891. 14 Hogue CW Jr, Palin CA, Kailasam R, et al: C- reactive protein levels and atrial fibrillation after cardiac surgery in women. Ann Thorac Surg 2006; 82: 97 102. 15 Ruchaud-Sparagano MH, Drost EM, Donnelly SC, et al: Potential pro-inflammatory effects of soluble E-selectin upon neutrophil function. Eur J Immunol 1998; 28: 80 89. 16 Nashef SAM, Roques F, Michel P, et al: European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16: 9 13. 17 Daxecker H, Raab M, Markovic S, et al: Endothelial adhesion molecule expression in an in vitro model of inflammation. Clin Chim Acta 2002; 325: 171 175. 18 Reinhart K, Bayer O, Brunkhorst F, et al: Markers of endothelial damage in organ dysfunction and sepsis. Crit Care Med 2002; 30(suppl): S302 S312. 19 Alvaro-González LC, Freijo-Guerrero MM, Sádaba-Garay F: Inflammatory mechanisms, arteriosclerosis and ischemic stroke: clinical data and perspectives. Rev Neurol 2002; 35: 452 462 [in Spanish, English abstract]. 20 Sablotzki A, Dehne MG, Mann V, et al: Plasma levels of selectins and interleukins in cardiovascular surgery using cardiopulmonary bypass. Thorac Cardiovasc Surg 1999; 47: 26 31. 21 Hayashi Y, Sawa Y, Nishimura M, et al: P- selectin participates in cardiopulmonary bypass-induced inflammatory response in association with nitric oxide and peroxynitrite production. J Thorac Cardiovasc Surg 2000; 120: 558 565. 22 Wildhirt SM, Schulze C, Schulz C, et al: Reduction of systemic and cardiac adhesion molecule expression after off-pump versus conventional coronary artery bypass grafting. Shock 2001; 16(suppl 1): 55 59. 23 Atalar E, Aytemir K, Haznedaroğlu I, et al: Increased plasma levels of soluble selectins in patients with unstable angina. Int J Cardiol 2000; 78: 69 73. 24 Fries JW, Williams AJ, Atkins RC, et al: Expression of VCAM-1 and E-selectin in an in vivo model of endothelial activation. Am J Pathol 1993; 143: 725 737. 25 Andresen TK, Svennevig JL, Videm V: Soluble VCAM-1 is a very early marker of endothelial cell activation in cardiopulmonary bypass. Perfusion 2002; 17: 15 21. 26 Blake GJ, Ridker PM: Novel clinical markers of vascular wall inflammation. Circ Res 2001; 89: 763 771. 27 Kubala L, Cíz M, Vondrácek J, et al: Perioperative and postoperative course of cytokines and the metabolic activity of neutrophils in human cardiac operations and heart transplantation. J Thorac Cardiovasc Surg 2002; 124: 1122 1129. Author s address for correspondence Dr Suat Canbaz Department of Cardiovascular Surgery, Medical Faculty, Trakya University, Edirne, TR 22030, Turkey. E-mails: scanbaz2001@yahoo.com scanbaz@trakya.edu.tr 1076