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Postoperative Inflammatory Reaction and Atrial Fibrillation: Simple Correlation or Causation?
Postoperative Inflammatory Reaction and Atrial Fibrillation: Simple Correlation or Causation? Amedeo Anselmi, MD, Gianfederico Possati, MD, and Mario Gaudino, MD Division of Cardiac Surgery, Catholic University, Rome, Italy
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Atrial fibrillation after cardiac operations is a source of morbidity and resource consumption. This systematic review of literature analyzes the current evidence on its pathophysiologic link with the systemic inflammatory response elicited by surgery and cardiopulmonary bypass. Meta-analysis of randomized studies on the effect of off-pump surgery or statin pre-treatment on the incidence of atrial fibrillation was performed. The concept of inflammation as a pathophysiologic determinant of post-
operative atrial fibrillation is supported by the literature. The modulation of post-cardiopulmonary bypass systemic inflammation will probably represent a major therapeutic goal in the prevention of postoperative atrial fibrillation. Statins seem to be the most promising pharmacological strategy.
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National Institutes of Health database (MEDLINE). According to a written protocol, the search was limited to abstracts published between January 1990 and May 2008. The abstracts had to be written in English, and the keywords entered for searching under the categories “search word” and “subject heading” included: atrial fibrillation, cardiac surgery, cardiopulmonary bypass, off-pump coronary bypass, cardioplegia, inflammation, C-reactive protein, interleukin (IL)-6, glucocorticoids, statins. Data that have not undergone peer review and proprietary studies were excluded. A total of 955 abstracts were screened by two observers. There were 859 publications that were discarded by title or abstract, or both, as they were unrelated to the scientific question. Another 103 publications were evaluated in detail by retrieval of the full-text. Of these, 11 were discarded with more than 1 publication focused on the same cohort of patients or unrelated to the scientific question. The review was mainly focused on articles produced regarding human subjects or human tissues, or both; nevertheless, evidence obtained from animal studies was also noted and discussed. The following were defined as markers of inflammation: C-reactive protein (CRP) and high-sensitivity CRP, pro-inflammatory cytokines (interleukin-6 [IL-6], IL-8, tumor necrosis factor-␣), indices of circulating white blood cell activation (peripheral white blood cell count and expression of monocyte adhesion receptor CD11b). The focus of the present report is new-onset AF occurring after cardiac surgery, in patients who were in sinus rhythm before the operation and had no history of preoperative AF. Patients had to be monitored either directly or by telemetry for at least 96 hours postoperatively. Clinical articles included in the present review had to comply with this definition (operational definition). Controlled, randomized trials focused on the effects of preoperative statin treatment on the incidence of postoperative AF were separately analyzed and compared by
trial fibrillation (AF) is the most common complication and rhythm disturbance occurring after cardiac surgery, with its incidence in contemporary series ranging between 27% and 40% [1–3]. Studies have questioned the idea that postoperative AF may increase the risk of operative death [4], but it has been associated with other postoperative morbidity [5] with consequent prolonged hospitalization and increased social costs [4, 6, 7]. As advanced age is universally reported as a predictor of new-onset AF, this problem is expected to grow in the near future. A huge amount of literature has been published regarding the predictors of postoperative AF [8, 9]. Although the pathogenesis of this complication is multifactorial and involves a multitude of clinical and intraoperative factors, evidence has been collected that the perioperative systemic inflammatory response elicited by cardiac surgery may stand among these elements [10, 11]. Postoperative AF as an inflammatory complication was regarded as an innovative concept with potential major clinical reflections. Such a relationship is characterized by an extremely composite interplay of systemic and myocardial pathophysiologic factors, which render challenging any analysis of the topic. The present article is intended to criticize and furnish a systematic review of the literature as evidence concerning the link between inflammation and AF after cardiac surgery. Several markers of systemic and myocardial inflammatory status have been proposed, and we aimed to discuss their reliability to predict the onset of postoperative AF. The main preventive strategies proposed in this perspective are analyzed by means of meta-analysis. A literature search was carried out in June 2008 in the PubMed National Center for Biotechnology Information,
Address correspondence to Dr Anselmi, Division of Cardiac Surgery, Catholic University, Largo A. Gemelli, 8, Rome, 00168, Italy; e-mail: [email protected].
© 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2009;88:326 –33) © 2009 by The Society of Thoracic Surgeons
0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2009.01.031
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means of meta-analysis. To be eligible, studies had to involve two groups of patients either treated with preoperative statins or not, and to have the incidence of new-onset AF after cardiac surgery as an endpoint. A fixed-effects calculation model was applied. Comprehensive Meta-Analysis Software, version 2.0 for Windows (Biostat Inc, Englewood, NJ) was used. Subsequently, recent (published in or after the year 2000) prospective, randomized trials evaluating off-pump versus on-pump coronary surgery were compared by means of metaanalysis. To be eligible, the studies had to include the occurrence of AF after coronary surgery among the endpoints. Data extraction from published studies was performed independently by two reviewers (AA and MG) with the aid of a data extraction sheet, and the extracted data were compared for agreement. Beta level was 0.1. L’Abbé plots were built for studies included in both meta-analyses to address heterogeneity. Tight clustering of studies indicated an adequate level of homogeneity (graphs not shown). The use of prophylactic anti-arrhythmic drugs (such as beta-blockers and amiodarone for the prevention of postoperative AF) was not addressed in the present review. Nonetheless, this represents a major issue that merits dedicated studies of in-depth analysis of relative importance versus anti-inflammatory strategies in preventing new-onset AF occurrence.
Overview of Observational Studies AF and Inflammatory Status in the Nonsurgical Patient Atrial structural remodeling may occur as a consequence of tissue inflammation. The evidence collected so far concerning the link between inflammation and the likelihood of atrial arrhythmias in nonoperative patients can be summarized as follows: (1) CRP was significantly increased in patients with atrial arrhythmias (particularly AF) compared with patients in sinus rhythm [12, 13]; (2) adjustment for baseline variables and use of antiarrhythmic drugs did not abolish such an association; (3) lower serum levels of high-sensitivity C-reactive protein were predictors of both successful cardioversion for AF and maintenance of sinus rhythm over time, whereas the predictive value of IL-6 in this respect is not well clarified [14 –16]; and (4) some studies indicated stepwise CRP elevation in patients with a higher AF burden (new-onset vs persisting AF) [12], although this issue is controversial [17]. It remains unclear whether reduced CRP levels would result in facilitated termination of AF, as no focused studies have been performed on this issue. In any case, in a controlled randomized study, the administration of vitamin C, known to be a potent antioxidant agent, significantly reduced the rate of recurrent AF after successful electrical cardioversion [18, 19]. Oxidative damage and inflammatory infiltrates coexist in atrial biopsies from patients with AF [20]. In the same study, the CRP levels were statistically lower in the group of patients who received ascorbate. In nonsurgical patients
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with chronic AF, both the oxidative stress and inflammatory alterations are associated with atrial electrical remodeling and contribute to auto-sustaining AF [21]. A chronic, low-grade systemic inflammatory status is associated with the genesis and perpetuation of lone AF in patients not subjected to surgery. Such a proinflammatory condition is apparently linked to underlying comorbidities, such as hypertension and coronary artery disease, with AF as the “response variable” in a cause-effect relationship [16].
Inflammatory Markers and Prediction of Postoperative AF: White Blood Cell Count and Activation and Proinflammatory Cytokines Cardiopulmonary bypass (CPB) and cardiac surgery are invariably associated with an acute systemic inflammatory reaction. The contact of the blood with foreign surfaces, the total length of the CPB circuit, the use of cardiotomy suction, blood-air interface, and the surgical stress itself have been regarded as the pathophysiologic determinants of such a condition. White blood cells are massively activated during CPB, and they release cytokines, proteases, metabolites of arachidonic acid, and reactive oxygen species both in the bloodstream and within the tissues [22, 23]. Inflammatory markers, including IL-6, IL-8, CRP, tumor necrosis factor-␣, and indices of neutrophil and platelet activation [24 –26], are significantly increased in the systemic bloodstream after CPB. The extreme manifestation of this condition is the systemic inflammatory response syndrome with the potential to evolve into multi-organ failure. Widespread endothelial activation and dysfunction is observed, with increased expression of adhesion molecules and impaired release of nitric oxide [27, 28]. After cardioplegic arrest, neutrophils transmigrate into the myocardium at the time of reperfusion; here they represent the major source of cytokines, inflammatory mediators, and reactive oxygen species [25]. Patients who have a higher postoperative leukocyte count are significantly more likely to develop new-onset AF [29, 30], whereas the preoperative count has no power to discriminate a subgroup of individuals at a higher risk of AF [30]. Patients developing new-onset AF had upregulated monocyte activation (significantly higher expression of CD11b) and a significantly higher monocyte and neutrophil blood count post-pump [31]. Transfusion with red blood cells during the early postoperative course is associated with an increased likelihood of new-onset AF despite adjustment for potential confounders [32]. Blood transfusion determines direct infusion of inflammatory mediators and elicits de novo pro-inflammatory response [33]. Thus, the acute inflammatory response associated with surgery rather than the preoperative general proinflammatory condition, is a pathophysiologic determinant of new-onset AF in patients operated on-pump and having sinus rhythm before the operation. Neutrophilderived, platelet-activating factor increases action potential duration [34]. Neutrophil-dependent inflammation increases both the inhomogeneity of conduction and the refractory period in atrial cardiomyocytes [35]. Intense
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tissue inflammation is characterized by inhomogeneous conduction, which may set the stage for multiple reentrant wavelets [35]. This represents an accepted theory for the genesis of AF [36]. The aforementioned events support: (1) different resistive properties and conduction velocities across spatially contiguous areas of the myocardial tissue, (2) inhomogeneous electrical conduction, and (3) pro-arrhythmic effect [37]. Advanced age and elevated IL-6 have been indicated as the strongest predictors of new-onset AF in patients operated both on-pump [11] or off-pump [38]. The IL-6 production reflects the degree of activation of polymorphonuclear cells and their ability to infiltrate the tissues. Elevated postoperative IL-6 release, which is prone to genetic modulation, showed good diagnostic performance in predicting AF, whereas the same could not be demonstrated for CRP [11]. The inflammatory mediator tumor necrosis factor-␣ downregulates the gap junction proteins, thus reducing cell coupling [39]. Myocardiocytes synthesize cytokine mRNAs as the myocardium is infiltrated by inflammatory cells; thus an intrinsic tissue inflammatory condition is triggered by CPB and it is auto-sustained [40].
Inflammatory Markers and Prediction of Postoperative AF: Oxidative Stress Mediators
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Oxidative stress is a feature of the atrial myocardial remodeling and is believed to sustain AF [41]. The CPB with cardioplegic arrest determines myocardial oxidative stress (increased oxidized glutathione and lipid peroxidation [42]). Release of reactive oxygen metabolites occurs within the myocardium as part of the ischemia-reperfusion injury [43]. Patients developing new-onset AF have increased systemic and myocardial oxidative stress compared with patients who remained in sinus rhythm [44, 45]. Such a difference has been straightforwardly linked with a differential expression of genes involved in the regulation of systemic and myocardial redox balance. Variability in the genetic response to CPB may thus predispose certain individuals to postoperative AF. Acute inflammatory and oxidative stress and tissue cytokines directly decrease the upstroke velocity of the action potential by reducing the transmembrane sodium currents [46]. Conduction velocity was anisotropically decreased in right atrial appendages by the application of arachidonic acid (precursor of the inflammatory mediators’ leukotrienes, thromboxanes, and prostaglandins) [47].
Inflammatory Markers and Prediction of Postoperative AF: CRP and High-Sensitivity C-Reactive Protein High-sensitivity C-reactive protein is probably the most reliable and reproducible among the inflammatory markers [48]. In a study of CPB-related acute phase reaction it was reported that the peak incidence of AF on the second to third postoperative day coincides with the peak of blood CRP [49]. Nonetheless, the theory postulating a direct causative role of CRP in favoring atrial arrhythmias (ie, binding to cell membrane phosphorylcholine and transmembrane ion exchange disturbances, “arrhythmo-
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genic” properties of CRP) was not ultimately supported by data. CRP has different kinetics in various cardiac operations [50]. Raised preoperative CRP levels have been associated with the development of new AF after cardiac surgery [51]. Controlled studies have questioned the idea that acutely raised CRP levels in response to surgery and CPB may correlate with the likelihood of AF [31, 52, 53]. The CRP should be regarded as a generic marker of inflammation. When preoperatively raised, it may reflect the global likelihood of developing new-onset AF, as in nonoperated patients affected by cardiovascular disease. It may also correlate with the occurrence of postoperative AF, but there is no evidence that this is more than simple association. The CRP should not influence the decision on pharmacological strategies to prevent postoperative AF in cardiac surgical patients who were in sinus rhythm before the operation. With respect to the triggering of AF, the perioperative tendency toward systemic inflammation seems to be irrelevant compared with the inflammatory response elicited by surgery and CPB.
Studies Designed to Suppress an Inflammatory Response Therapeutic Implications: The “No-Pump” Approach Versus the “Glucocorticoid” Approach On the basis of the previous evidence, the reduction of the systemic inflammatory response is expected to be associated with less risk of new-onset AF. Two different methodological approaches have been pursued: offpump surgery and pharmacological modulation of the inflammatory response after on-pump operations. Coronary surgery without CPB is believed to elicit lesser systemic surge of inflammatory mediators than on-pump interventions [54]. Nonetheless, the clinical benefits of such a reduction in the systemic inflammatory response have not been conclusively demonstrated (Table 1). Several clinical series report no statistical association between off-pump surgery and less incidence of new-onset AF. However, such articles are often limited by their retrospective nature, or by incomplete adjustment for potential confounders, or for the coexistence of paroxysmal–persisting AF before surgery [55], or by the very limited sample size [56, 57]. Others evidenced different time distributions in the onset of AF in off-pump versus on-pump patients [58], which may indicate that different pathophysiologic means are at the root of AF genesis in these opposite circumstances. Because all studies showed at least a nonsignificant trend toward less AF incidence after off-pump surgery [59, 60, 61, 62], one should hypothesize that: (1) the advantage in terms of risk of AF after off-pump surgery, if present, may be little, and (2) insufficient statistical power and failure to adjust for confounding factors may be the reason for lack of statistical significance. Controlled randomized investigations of off-pump versus on-pump coronary surgery have indicated CPB plus cardioplegic arrest as the main predictors of new-onset
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Table 1. Studies Evaluating the Incidence of Atrial Fibrillation After On-Pump Versus Off-Pump Coronary Surgery Study Enc and colleagues [55] (2004) Siebert and colleagues [58] (2003) Scherer and colleagues [56] (2006) Murphy and colleagues [64] (2003) BHACAS 1—Ascione and colleagues [63] (2000) Boyd and colleagues [65] (1999) Van Belleghem and colleagues [66] (2003) Czerny and colleagues [59] (2001) BHACAS 2—Angelini and colleagues [60] (2002) Zamvar and colleagues [61] (2002) Légaré and colleagues [62] (2004)
Type of Study
No. of Patients
Mean Age
p Value*
Retrospective Retrospective Retrospective Prospective randomized Prospective randomized Retrospective Retrospective Prospective randomized Prospective randomized Prospective randomized Prospective randomized
670 1,067 72 200 200 90 458 80 201 60 300
60–61 59–61 57–66 NA 63 74 65–67 64–67 61–63 61–63 62–63
0.65 0.45 NS ⬍ 0.001 0.001 ⬍ 0.05 0.010 NS 0.017 0.12 0.20
* For difference in observed incidence of atrial fibrillation (AF) for on-pump versus off-pump.
AF [63, 64]. The reduction in the likelihood of AF after off-pump surgery may be more evident in the elderly surgical candidates [65] who are inherently more prone to AF, and in high-risk individuals with multiple preoperative comorbidities [66]. Finally, in a comprehensive review and meta-analysis of studies comparing off-pump versus on-pump surgery in the elderly [67], it was confirmed that the off-pump strategy is associated with a significantly decreased incidence of new-onset AF. This conclusion emerged despite the fact that 9 of 11 studies evidenced a nonsignificant tendency toward less incidence of postoperative AF in the off-pump cohorts. This is in keeping with the conclusions of the other two meta-analyses [68, 69]. Our meta-analysis of recent randomized controlled trials having the occurrence of postoperative AF as a study endpoint confirms these results, indicating a statistically significant advantage in terms of new-onset AF incidence if the pump is avoided (odds ratio, 0.427; 95% confidence interval, 0.306 to 0.597; total, 841 patients studied) (Fig 1). Should we presume that the importance of CPB-related inflammation in triggering AF is secondary compared with surgical stress alone? As an inherent limitation in the clinical series of on-pump coronary surgery, it must be considered that it is difficult to distinguish the weight of the systemic inflammatory reaction from that of atrial ischemia-reperfusion, cannulation, and incision in the genesis of AF. The degree of atrial myocardial inflammation is reported to increase with increasing the invasiveness of surgery; the extent of
atrial manipulation may vary and can influence the probability of AF [70]. Innovative CPB systems, which are more biocompatible and have been associated with a dramatic reduction in the entity of the inflammatory response [71, 72], should be investigated as potential tools to decrease the incidence of new-onset AF. Administration of methylprednisolone has resulted in decreased inhomogeneity of atrial conduction [35], and ultimately in less incidence or duration of AF in animal models of cardiac surgery [47]. In randomized studies, a single dose of dexamethasone (0.6 mg/kg or 1 g) at induction of anesthesia, could achieve a statistically significant lower rate of new-onset AF [73]. Lower dexamethasone doses did not prove beneficial in this respect. A critical issue is presumably the drug dose load, the number of doses, and the time of administration [74]. Despite modest statistical power, a combination of methylprednisolone (1 g) before surgery plus dexamethasone (4 mg every 6 hours) thereafter, significantly reduced the incidence of new-onset AF in a randomized investigation. A large, multicenter, randomized trial of these studies confirmed the efficacy of glucocorticoid treatment to reduce the cases of postoperative AF [75, 76]. Drug administration protocols including the first 48 to 72 postoperative hours, in which the systemic inflammatory reaction to CPB is more evident, are thus reported to obtain better results. The previous data represent an indirect criterion substantiating the pathogenetic link between inflammation and new-onset AF. Aside from Fig 1. Intervention effect of off-pump strategy versus on-pump technique for coronary surgery on incidence of postoperative atrial fibrillation (AF) in prospective randomized trials (forest plot). Error bars indicate 95% confidence intervals (CIs).
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NS ⫽ nonsignificant.
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Table 2. Studies Evaluating the Effects of Statin Treatment on the Incidence of Postoperative Atrial Fibrillation Study Patti and colleagues [89] (2006) Marin and colleagues [86] (2006) Ozaydin and colleagues [87] (2007) Mariscalco and colleagues [88] (2007) Lertsburapa and colleagues [84] (2008) Kourliouros and colleagues [90] (2008)
Type of Study
No. of Patients
p Value*
Prospective randomized Prospective nonrandomized Prospective nonrandomized Retrospective Prospective randomized Retrospective
200 234 362 405 555 623
0.003 0.024 0.03 0.021 0.035 ⬍ 0.001
* For difference in observed incidence of atrial fibrillation for statin-treated versus non-statin-treated group.
this, the question remains open as to whether the use of glucocorticoids to prevent AF in cardiac surgical patients is clinically worthwhile. No significant increase in major morbidity has been reported in most studies [77]; however, minor postoperative morbidity may rise. Such issues deserve investigation in view of the larger application. Thus, both the “no-pump” approach and the “glucocorticoid” approach present inherent limitations. The CPB can not be avoided in the vast majority of cardiac operations. Off-pump coronary artery bypass grafting remains a challenging procedure in multivessel disease, and its applicability is limited by surgeon-dependent factors (ie, specific training required with a long learning curve) and by nonsurgeon-dependent factors (ie, the possibility of hemodynamic instability and revascularization required for obtuse marginal and posterolateral branches). In addition, the advantages of off-pump coronary artery bypass grafting in terms of less AF incidence in the real world are probably lower than theoretically expected. Steroids are reportedly efficacious, but significant doses are required and perioperative morbidity may increase. Reports on other anti-inflammatory agents are scattered and evidence in humans are lacking. REVIEWS
Statins, Inflammatory Status, and AF The 3-hydroxy-3-methyl-glutaryl coenzyme-A reductase inhibitors, known as statins, were reported to achieve a number of pharmacological effects beyond their primary lipid-lowering action, including anti-inflammatory properties (pleiotropic effects) [78]. Simvastatin, pravastatin, and atorvastatin reduced the high-sensitivity C-reactive protein levels, but not the IL-6 levels, during primary prevention in dyslipidemic patients [79]. Statins improve nitric oxide-dependent endothelial function [80] and have anti-oxidant properties [81], as well as antiproliferative effects, although such effects are still to be demonFig 2. Intervention effect of preoperative statin treatment versus controls on incidence of atrial fibrillation (AF) after cardiac surgery in prospective randomized trials (forest plot). Error bars indicate 95% confidence intervals (CIs).
strated in the acute setting of inflammatory reaction to CPB. Patients with lone AF who had successful cardioversion were more likely to maintain sinus rhythm at follow-up if treated with statins [82]. The use of statins in patients with stable coronary artery disease is protective against development of new AF [83]. Preoperative statin treatment reduced the postoperative incidence of AF in a cohort of patients subjected to thoracic off-pump noncardiac surgery [84]. Such effect was independent of the systemic release of inflammatory markers (CRP/IL-6), thus suggesting that the mechanisms through which statins exert their anti-arrhythmic properties lie at the tissue level. Statins may reduce the incidence of newonset AF, even in patients administered with prophylactic beta-blockers and amiodarone [85]. Atorvastatin decreased the release of inflammatory markers and neutrophil activation after CPB [85]. Statin treatment initiated before on-pump surgery was then reported as protective against the development of AF [86 – 88]. This observation was confirmed in a randomized trial [89]. In this study, the pre-treatment (atorvastatin, 40 mg per day, administered irrespective of the cholesterol level) was standardized to a 7-day preoperative duration, and it was a multivariable predictor of reduced risk of new-onset AF. The efficacy of statins in preventing the onset of AF may be dose-dependent [90]. Two controlled randomized studies focused on the effects of statin pre-treatment on the occurrence of postoperative AF were included in the meta-analysis (total, 755 patients studied) (Table 2). Although the small number of available studies is potentially a study limitation, results indicate that statin pre-treatment is effective in preventing postoperative AF (odds ratio, 0.572; 95% confidence interval, 0.421 to 0.777) (Fig 2). Statins may be realistically applied to this purpose in daily clinical practice. However, an ongoing investigation is required,
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as the small number of studies available up to now represents a limitation of the present analysis. Statins have not been demonstrated to have any direct anti-arrhythmic effect by pharmacological activity on ion channels and transmembrane currents. Conversely, the reduction of new-onset AF associated with statins may be ascribed to the modulation of various pathophysiologic mechanisms which favor the onset of AF. The systemic and myocardial inflammation and the oxidative balance are reasonable among such mechanisms.
Comment The concept that inflammation is a causative pathophysiologic element of postoperative AF is supported by recent literature. Such a link displays different features in nonoperated patients with cardiovascular disease versus patients undergoing cardiac surgery. In the latter case, the acute systemic inflammatory reaction due to CPB and generalized surgical trauma is a main determinant of new-onset AF, although it is difficult to quantify its relative importance in comparison with other factors, such as direct surgical trauma of the atria (ie, incision, cannulation, and so forth). Nonetheless, the modulation of inflammation will probably represent a major therapeutic goal in the short term and a promising pathway. Among the strategies attempted, statins currently represent the most reasonable pathway in the clinical treatment-outcome balance to reduce the incidence of AF after cardiac surgery. Further investigations to conclusively demonstrate their efficacy are warranted.
References 1. Hogue CW, Creswell LL, Gutterman DD, Fleisher LA. Epidemiology, mechanisms and risks: American college of chest physicians guidelines for the prevention and management of postoperative atrial fibrillation. Chest 2005;128:9 –16. 2. Zaman AG, Archbold RA, Helft G, Paul EA, Curzen NP, Mills PG. Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification. Circulation 2000;101:1403– 8. 3. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004;291:1720 –9. 4. Kalavrouziotis D, Buth KJ, Ali IS. The impact of new-onset atrial fibrillation on in-hospital mortality following cardiac surgery. Chest 2007;131:833–9. 5. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061–73. 6. Tamis JE, Steinberg JS. Atrial fibrillation independently prolongs hospital stay after coronary artery bypass surgery. Clin Cardiol 2000;33:155–9. 7. Tamis-Holland JE, Kowalski M, Rill V, Firoozi K, Steinberg JS. Patterns of atrial fibrillation after coronary artery bypass surgery. Ann Noninvasive Electrocardiol 2006;11:139 – 44. 8. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 1996;94:390 –7. 9. Magee MJ, Herbert MA, Dewey TM, et al. Atrial fibrillation after coronary artery bypass surgery: development of a predictive risk algorithm. Ann Thorac Surg 2007;83:1707–12. 10. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003; 108:3006 –10.
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11. Gaudino M, Andreotti F, Zamparelli R, et al. The -174G/C inetrleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation 2003; 108:195–9. 12. 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 –91. 13. Hatzinikolau-Kotsakou E, Tziakas D, Hotidis A, Stakos D, Floros D, Mavridis A. Relation of C-reactive protein to the first onset and the recurrence rate in lone atrial fibrillation. Am J Cardiol 2006;97:659 – 61. 14. Watanabe E, Arakawa T, Uchiyama T, Kodama I, Hishida H. High-sensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion. Int J Cardiol 2006;108:346 –53. 15. Acevedo M, Corbalàn R, Braun S, Pereira J, Navarrete C, Gonzalez I. C-reactive protein and atrial fibrillation: evidence for the presence of inflammation in the perpetuation of the arrhythmia. Int J Cardiol 2006;108:326 –31. 16. Tveit A, Seljeflot I, Grundvold I, Abdelnoor M, Smith P, Arnesen H. Effect of candesartan and various inflammatory markers on maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation. Am J Cardiol 2007;1999: 1544 – 8. 17. Gedikli O, Dogan A, Altuntas I, Altinbas A, Ozaydin M, Akturk O. Inflammatory markers according to types of atrial fibrillation. Int J Cardiol 2007;120:193–7. 18. Conway D, Biggins P, Hughes E, Lip G. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol 2004;43: 2075– 82. 19. Korantzopoulos P, Kolettis TM, Kountouris E, et al. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. Int J Cardiol 2005; 102:321– 6. 20. Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001;104:174 – 80. 21. Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit 2003;9: RA225–9. 22. Cosgrave J, Foley JB, Flavin R, et al. Preoperative atrial histological changes are not associated with postoperative atrial fibrillation. Cardiovasc Pathol 2006;15:213–7. 23. Kawahito K, Kobayashi E, Ohmori M, et al. Enhanced responsiveness of circulatory neutrophils after cardiopulmonary bypass: increased aggregability and superoxide production capacity. Artif Organs 2000;24:37– 42. 24. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophyisiology and treatment: an update. Eur J Cardiothorac Surg 2002;21:232– 44. 25. Zahler S, Massoudy P, Hartl H, Hahnel C, Meinser H, Becker BF. Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass. Cardiovasc Res 1999;41:722–30. 26. te Velthuis H, Janse PG, Oudemans-van Straaten HM, Sturk A, Eijsman L, Wildevuur CR. Myocardial performance in elderly patients after cardiopulmonary bypass is suppressed by tumor necrosis factor. J Thorac Cardiovasc Surg 1995;110: 1663–9. 27. Grunenfelder J, Zund G, Schoeberlein A, et al. Modified ultrafiltration lowers adhesion molecules and cytokine levels after cardiopulmonary bypass without clinical relevance in adults. Eur J Cardiothorac Surg 2000;17:77– 83. 28. Toprak V, Sirin BH, Tok D, Ozbilgin K, Saribulbul O. The effect of cardiopulmonary bypass on the expression of inducible nitric oxide synthase, endothelial nitric oxide synthase, and vascular endothelial growth factor in the internal mammary artery. J Cardiothorac Vasc Anesth 2006;20:63–7.
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29. Abdelhadi RH, Gurm HS, Van Wagoner D, Chung MK. Relation of an exaggerated rise in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively. Am J Cardiol 2004;93: 1176 – 8. 30. Lamm G, Auer J, Weber T, Berent R, Nq C, Eber B. Postoperative white blood cell count predicts atrial fibrillation after cardiac surgery. J Cardiothorac Vasc Anesth 2006; 20:51– 6. 31. Fontes ML, Mathew JP, Rinder HM, Zelterman D, Smith BR, Rinder CS; Multicenter study of perioperative ischemia (McSPI) research group. Atrial fibrillation after cardiac surgery/cardiopulmonary bypass is associated with monocyte activation. Anesth Analg 2005;101:17–23. 32. Koch CG, Li L, Van Wagoner D, Duncan AI, Gillinov AM, Blackstone EH. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 2006;82:1747–57. 33. Fransen E, Maessen J, Dentener M, Senden N, Buurman W. Impact of blood transfusions of inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999;116: 1233–9. 34. Hoffman BF, Feinmark SJ, Guo SD. Electrophysiologic effects of interactions between activated canine neutrophils and cardiac myocytes. J Cardiovasc Electrophysiol 1997;8:679 – 87. 35. Ishii Y, Schuessler RB, Gaynor SL, et al. Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 2005;111:2881– 8. 36. Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando: Grune & Stratton Inc 1985:265–75. 37. Dupont E, Ko YS, Rothery S, et al. The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation 2001;103:842–9. 38. Ishida K, Kimura F, Imamaki M, et al. Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 2006;29: 501–5. 39. Fernandez-Cobo M, Gingalewski C, Drujan D, De Maio A. Downergulation of connexin 43 gene expression in rat heart during inflammation. The role of tumor necrosis factor. Cytokine 1999;11:216 –24. 40. Anselmi A, Abbate A, Girola F, et al. Myocardial ischemia, stunning, inflammation and apoptosis during cardiac surgery: a review of evidence. Eur J Cardiothorac Surg 2004;25: 304 –11. 41. Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and the left atrial appendage: role of NADPH and xanthine oxidases. Circulation 2005;112:1266 –73. 42. De Vecchi E, Pala MG, Di Credico G, et al. Relation between left ventricular function and oxidative stress in patients undergoing bypass surgery. Heart 1998;79:242–7. 43. Wan S, Yim AP, Wong CK, et al. Expression of FHL2 and cytokine messenger RNAs in human myocardium after cardiopulmonary bypass. Int J Cardiol 2002;86:265–72. 44. Ramlawi B, Out H, Mieno S. Oxidative stress and atrial fibrillation after cardiac surgery: a case-control study. Ann Thorac Surg 2007;84:1166 –73. 45. Carnes CA, Chung MK, Nakayama T, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001;89:E32– 8. 46. Wang GK, Wang SY. Modifications of human cardiac sodium channel gating by UVA light. J Membr Biol 2002;189: 153– 65. 47. Tselentakis EV, Woodford E, Chandy J, Gaudette GR, Saltman AE. Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. J Surg Res 2006;135:68 –75.
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48. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation: part 1. Circulation 2003;108:1917–23. 49. 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;96:3542– 8. 50. Gaudino M, Nasso G, Andreotti F, et al. Preoperative C-reactive protein level and outcome following coronary surgery. Eur J Cardiothorac Surg 2002;22:521– 6. 51. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk factor for atrial fibrillation after myocardial revascularization. Ann Thorac Surg 2005;79:1530 –35. 52. 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. 53. Ahlsson AJ, Bodin L, Lundblad OH, Englund AG. Postoperative atrial fibrillation is not correlated to C-reactive protein. Ann Thorac Surg 2007;83:1332–7. 54. Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999;68:52– 6. 55. Enc Y, Ketenci B, Ozsoy D, et al. Atrial fibrillation after surgical revascularization: is there any difference between on-pump and off-pump? Eur J Cardiothorac Surg 2004;26: 1129 –33. 56. Scherer M, Sirat AS, Dogan S, Aybeck T, Moritz A, WimmerGreinecker G. Does totally endoscopic access for off-pump cardiac surgery influence the incidence of postoperative atrial fibrillation in coronary artery bypass grafting? A preliminary report. Cardiovasc Eng 2006;6:118 –21. 57. Abreu JE, Reilly J, Salzano RP, Khachane VB, Jekel JF, Clyne CA. Comparison of frequencies of atrial fibrillation after coronary artery bypass grafting with and without the use of cardiopulmonary bypass. Am J Cardiol 1999;83:775– 6. 58. Siebert J, Lewicki L, Mlodnicki M, et al. Atrial fibrillation after conventional and off-pump coronary artery bypass grafting: two opposite trends in timing of atrial fibrillation occurrence? Med Sci Monit 2003;9:CR137– 41. 59. Czerny M, Baumer H, Kilo J, et al. Complete revascularization in coronary artery bypass grafting with and without cardiopulmonary bypass. Ann Thorac Surg 2001;71:165–9. 60. Angelini DG, Taylor FC, Reeves BC, Ascione R. Early and midterm outcome of after off-pump and on-pump surgery in beating heart against cardioplegic arrest studies (BHACAS 1 and 2): a pooled analysis of two randomized controlled trials. Lancet 2002;359:1194 –9. 61. Zamvar V, Williams D, Hall J, et al. Assessment of neurocognitive impairment after off-pump and on-pump technique for coronary artery bypass graft surgery: a prospective randomized controlled trial. BMJ 2002;325:1268. 62. Légaré JF, Buth KJ, King S et al. Coronary bypass surgery performed off-pump may not result in lower in-hospital morbidity than coronary artery bypass grafting performed on-pump. Circulation 2004;109:887–92. 63. Ascione R, Caputo M, Calori G, Lloyd CT, Underwood MJ, Angelini GD. Predictor of atrial fibrillation after conventional and beating heart coronary surgery: a prospective, randomized study. Circulation 2000;102:1530 –5. 64. Murphy GJ, Ascione R, Caputo M, Angelini GD. Operative factors that contribute to postoperative atrial fibrillation: insights from a prospective randomized trial. Card Electrophysiol Rev 2003;7:136 –9. 65. Boyd WD, Desai ND, Del Rizzo DF, Novick RJ, McKenzie FN, Menkis AH. Off-pump surgery decreases postoperative complications and resource utilization in the elderly. Ann Thorac Surg 1999;68:1490 –3. 66. Van Belleghem Y, Caes F, Van Overbeke H, Moerman A, Van Nooten G. Off-pump coronary surgery: surgical strategy for the high-risk patient. Cardiovasc Surg 2003;11:75–9.
REVIEW ANSELMI ET AL POSTOPERATIVE INFLAMMATION AND ATRIAL FIBRILLATION
67. Panesar SS, Athanasiou T, Nair S, et al. Early outcomes in the elderly: a meta-analysis of 4921 patients undergoing coronary artery bypass grafting— comparison between offpump and on-pump techniques. Heart 2006;92:1808 –16. 68. Reston JT, Tregear SJ, Turkelson CM. Meta-analysis of short-term and mid-term outcomes following off-pump coronary artery bypass grafting. Ann Thorac Surg 2003;76: 1510 –5. 69. Cheng DC, Bainbridge D, Martin JE, Novick RJ. The evidence-based perioperative clinical outcomes research group. Does off-pump coronary artery bypass reduce mortality, morbidity and resource utilization when compared with conventional coronary artery bypass? A meta-analysis of randomized trials. Anesthesiology 2005;102:188 –203. 70. Stamou SC, Dangas G, Hill PC. Atrial fibrillation after beating heart surgery. Am J Cardiol 2000;86:64 –7. 71. Fromes Y, Gaillard D, Ponzio O, et al. Reduction of the inflammatory response following coronary bypass grafting with total minimal extracorporeal circulation. Eur J Cardiothorac Surg 2002;22:527–33. 72. Pransongsukarn K, Abel JG, Jamieson WR, et al. The effects of steroids on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting surgery: a prospective randomized trial. J Thorac Cardiovasc Surg 2005;130: 93– 8. 73. Yared JP, Starr NJ, Torres FK, et al. Effects of a single dose, postinduction dexamethasone on recovery after cardiac surgery. Ann Thorac Surg 2000;69:1420 – 4. 74. Yared JP, Bakri MH, Erzurum SC, et al. Effect of dexamethasone on atrial fibrillation after cardiac surgery: prospective, randomized, double-blind, placebo-controlled trial. J Cardiothorac Vasc Anesth 2007;21:68 –75. 75. Rubens FD, Nathan H, Labow R, et al. Effects of methylprednisolone and a biocompatible copolymer circuit on blood activation during cardiopulmonary bypass. Ann Thorac Surg 2005;79:655– 65. 76. Patel AA, White CM, Shah SA, Dale KM, Kluger J, Coleman CI. The relationship between statin use and atrial fibrillation. Curr Med Res Opin 2007;23:1177– 85. 77. Halvorsen P, Raeder J, White PF, et al. The effect of dexamethasone on side effects after coronary revascularization procedures. Anesth Analg 2003;96:1578 – 83. 78. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Deveraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase
79. 80. 81. 82.
83. 84.
85.
86. 87. 88.
89.
90.
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inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933–5. Halonen J, Halonen P, Jarvinen O, et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA 2007;297:1526 –7. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129 –35. Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108:426 –31. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003; 92:1343–5. Chello M, Patti G, Candura D, et al. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery. Crit Care Med 2006;34:660 –7. Lertsburapa K, White CM, Kluger J, Faheem O, Hammond J, Coleman CI. Preoperative statins for the prevention of atrial fibrillation after cardiothoracic surgery. J Thorac Cardiovasc Surg 2008;135:405–11. Amar D, Zhang H, Heerdt P, Park B, Fleisher M, Thaler H. Statin use is associated with a reduction in atrial fibrillation after noncardiac thoracic surgery independent of C-reactive protein. Chest 2005;128:3421–7. Marin F, Pascual DA, Roldan V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 2006;97:55– 60. Ozaydin M, Dogan A, Varol E, et al. Statin use before bypass surgery decreases the incidence and shortens the duration of postoperative atrial fibrillation. Cardiology 2007;107:117–21. Mariscalco G, Lorusso R, Klersy C, et al. Observational study on the beneficial effect of preoperative statins in reducing atrial fibrillation after coronary surgery. Ann Thorac Surg 2007;84:1158 – 64. Patti G, Chello M, Candura D, et al. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (atorvastatin for reduction of myocardial dysrythmia after cardiac surgery) study. Circulation 2006;114:1455– 61. Kourliouros A, De Souza A, Roberts N, et al. Dose-related effect of statins on atrial fibrillation after cardiac surgery. Ann Thorac Surg 2008;85:1515–20. REVIEWS
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Atrial fibrillation after cardiac operations is a source of morbidity and resource consumption. This systematic review of literature analyzes the current evidence on its pathophysiologic link with the systemic inflammatory response elicited by surgery and cardiopulmonary bypass. Meta-analysis of randomized studies on the effect of off-pump surgery or statin pre-treatment on the incidence of atrial fibrillation was performed. The concept of inflammation as a pathophysiologic determinant of post-
operative atrial fibrillation is supported by the literature. The modulation of post-cardiopulmonary bypass systemic inflammation will probably represent a major therapeutic goal in the prevention of postoperative atrial fibrillation. Statins seem to be the most promising pharmacological strategy.
A
National Institutes of Health database (MEDLINE). According to a written protocol, the search was limited to abstracts published between January 1990 and May 2008. The abstracts had to be written in English, and the keywords entered for searching under the categories “search word” and “subject heading” included: atrial fibrillation, cardiac surgery, cardiopulmonary bypass, off-pump coronary bypass, cardioplegia, inflammation, C-reactive protein, interleukin (IL)-6, glucocorticoids, statins. Data that have not undergone peer review and proprietary studies were excluded. A total of 955 abstracts were screened by two observers. There were 859 publications that were discarded by title or abstract, or both, as they were unrelated to the scientific question. Another 103 publications were evaluated in detail by retrieval of the full-text. Of these, 11 were discarded with more than 1 publication focused on the same cohort of patients or unrelated to the scientific question. The review was mainly focused on articles produced regarding human subjects or human tissues, or both; nevertheless, evidence obtained from animal studies was also noted and discussed. The following were defined as markers of inflammation: C-reactive protein (CRP) and high-sensitivity CRP, pro-inflammatory cytokines (interleukin-6 [IL-6], IL-8, tumor necrosis factor-␣), indices of circulating white blood cell activation (peripheral white blood cell count and expression of monocyte adhesion receptor CD11b). The focus of the present report is new-onset AF occurring after cardiac surgery, in patients who were in sinus rhythm before the operation and had no history of preoperative AF. Patients had to be monitored either directly or by telemetry for at least 96 hours postoperatively. Clinical articles included in the present review had to comply with this definition (operational definition). Controlled, randomized trials focused on the effects of preoperative statin treatment on the incidence of postoperative AF were separately analyzed and compared by
trial fibrillation (AF) is the most common complication and rhythm disturbance occurring after cardiac surgery, with its incidence in contemporary series ranging between 27% and 40% [1–3]. Studies have questioned the idea that postoperative AF may increase the risk of operative death [4], but it has been associated with other postoperative morbidity [5] with consequent prolonged hospitalization and increased social costs [4, 6, 7]. As advanced age is universally reported as a predictor of new-onset AF, this problem is expected to grow in the near future. A huge amount of literature has been published regarding the predictors of postoperative AF [8, 9]. Although the pathogenesis of this complication is multifactorial and involves a multitude of clinical and intraoperative factors, evidence has been collected that the perioperative systemic inflammatory response elicited by cardiac surgery may stand among these elements [10, 11]. Postoperative AF as an inflammatory complication was regarded as an innovative concept with potential major clinical reflections. Such a relationship is characterized by an extremely composite interplay of systemic and myocardial pathophysiologic factors, which render challenging any analysis of the topic. The present article is intended to criticize and furnish a systematic review of the literature as evidence concerning the link between inflammation and AF after cardiac surgery. Several markers of systemic and myocardial inflammatory status have been proposed, and we aimed to discuss their reliability to predict the onset of postoperative AF. The main preventive strategies proposed in this perspective are analyzed by means of meta-analysis. A literature search was carried out in June 2008 in the PubMed National Center for Biotechnology Information,
Address correspondence to Dr Anselmi, Division of Cardiac Surgery, Catholic University, Largo A. Gemelli, 8, Rome, 00168, Italy; e-mail: [email protected].
© 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2009;88:326 –33) © 2009 by The Society of Thoracic Surgeons
0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2009.01.031
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means of meta-analysis. To be eligible, studies had to involve two groups of patients either treated with preoperative statins or not, and to have the incidence of new-onset AF after cardiac surgery as an endpoint. A fixed-effects calculation model was applied. Comprehensive Meta-Analysis Software, version 2.0 for Windows (Biostat Inc, Englewood, NJ) was used. Subsequently, recent (published in or after the year 2000) prospective, randomized trials evaluating off-pump versus on-pump coronary surgery were compared by means of metaanalysis. To be eligible, the studies had to include the occurrence of AF after coronary surgery among the endpoints. Data extraction from published studies was performed independently by two reviewers (AA and MG) with the aid of a data extraction sheet, and the extracted data were compared for agreement. Beta level was 0.1. L’Abbé plots were built for studies included in both meta-analyses to address heterogeneity. Tight clustering of studies indicated an adequate level of homogeneity (graphs not shown). The use of prophylactic anti-arrhythmic drugs (such as beta-blockers and amiodarone for the prevention of postoperative AF) was not addressed in the present review. Nonetheless, this represents a major issue that merits dedicated studies of in-depth analysis of relative importance versus anti-inflammatory strategies in preventing new-onset AF occurrence.
Overview of Observational Studies AF and Inflammatory Status in the Nonsurgical Patient Atrial structural remodeling may occur as a consequence of tissue inflammation. The evidence collected so far concerning the link between inflammation and the likelihood of atrial arrhythmias in nonoperative patients can be summarized as follows: (1) CRP was significantly increased in patients with atrial arrhythmias (particularly AF) compared with patients in sinus rhythm [12, 13]; (2) adjustment for baseline variables and use of antiarrhythmic drugs did not abolish such an association; (3) lower serum levels of high-sensitivity C-reactive protein were predictors of both successful cardioversion for AF and maintenance of sinus rhythm over time, whereas the predictive value of IL-6 in this respect is not well clarified [14 –16]; and (4) some studies indicated stepwise CRP elevation in patients with a higher AF burden (new-onset vs persisting AF) [12], although this issue is controversial [17]. It remains unclear whether reduced CRP levels would result in facilitated termination of AF, as no focused studies have been performed on this issue. In any case, in a controlled randomized study, the administration of vitamin C, known to be a potent antioxidant agent, significantly reduced the rate of recurrent AF after successful electrical cardioversion [18, 19]. Oxidative damage and inflammatory infiltrates coexist in atrial biopsies from patients with AF [20]. In the same study, the CRP levels were statistically lower in the group of patients who received ascorbate. In nonsurgical patients
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with chronic AF, both the oxidative stress and inflammatory alterations are associated with atrial electrical remodeling and contribute to auto-sustaining AF [21]. A chronic, low-grade systemic inflammatory status is associated with the genesis and perpetuation of lone AF in patients not subjected to surgery. Such a proinflammatory condition is apparently linked to underlying comorbidities, such as hypertension and coronary artery disease, with AF as the “response variable” in a cause-effect relationship [16].
Inflammatory Markers and Prediction of Postoperative AF: White Blood Cell Count and Activation and Proinflammatory Cytokines Cardiopulmonary bypass (CPB) and cardiac surgery are invariably associated with an acute systemic inflammatory reaction. The contact of the blood with foreign surfaces, the total length of the CPB circuit, the use of cardiotomy suction, blood-air interface, and the surgical stress itself have been regarded as the pathophysiologic determinants of such a condition. White blood cells are massively activated during CPB, and they release cytokines, proteases, metabolites of arachidonic acid, and reactive oxygen species both in the bloodstream and within the tissues [22, 23]. Inflammatory markers, including IL-6, IL-8, CRP, tumor necrosis factor-␣, and indices of neutrophil and platelet activation [24 –26], are significantly increased in the systemic bloodstream after CPB. The extreme manifestation of this condition is the systemic inflammatory response syndrome with the potential to evolve into multi-organ failure. Widespread endothelial activation and dysfunction is observed, with increased expression of adhesion molecules and impaired release of nitric oxide [27, 28]. After cardioplegic arrest, neutrophils transmigrate into the myocardium at the time of reperfusion; here they represent the major source of cytokines, inflammatory mediators, and reactive oxygen species [25]. Patients who have a higher postoperative leukocyte count are significantly more likely to develop new-onset AF [29, 30], whereas the preoperative count has no power to discriminate a subgroup of individuals at a higher risk of AF [30]. Patients developing new-onset AF had upregulated monocyte activation (significantly higher expression of CD11b) and a significantly higher monocyte and neutrophil blood count post-pump [31]. Transfusion with red blood cells during the early postoperative course is associated with an increased likelihood of new-onset AF despite adjustment for potential confounders [32]. Blood transfusion determines direct infusion of inflammatory mediators and elicits de novo pro-inflammatory response [33]. Thus, the acute inflammatory response associated with surgery rather than the preoperative general proinflammatory condition, is a pathophysiologic determinant of new-onset AF in patients operated on-pump and having sinus rhythm before the operation. Neutrophilderived, platelet-activating factor increases action potential duration [34]. Neutrophil-dependent inflammation increases both the inhomogeneity of conduction and the refractory period in atrial cardiomyocytes [35]. Intense
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tissue inflammation is characterized by inhomogeneous conduction, which may set the stage for multiple reentrant wavelets [35]. This represents an accepted theory for the genesis of AF [36]. The aforementioned events support: (1) different resistive properties and conduction velocities across spatially contiguous areas of the myocardial tissue, (2) inhomogeneous electrical conduction, and (3) pro-arrhythmic effect [37]. Advanced age and elevated IL-6 have been indicated as the strongest predictors of new-onset AF in patients operated both on-pump [11] or off-pump [38]. The IL-6 production reflects the degree of activation of polymorphonuclear cells and their ability to infiltrate the tissues. Elevated postoperative IL-6 release, which is prone to genetic modulation, showed good diagnostic performance in predicting AF, whereas the same could not be demonstrated for CRP [11]. The inflammatory mediator tumor necrosis factor-␣ downregulates the gap junction proteins, thus reducing cell coupling [39]. Myocardiocytes synthesize cytokine mRNAs as the myocardium is infiltrated by inflammatory cells; thus an intrinsic tissue inflammatory condition is triggered by CPB and it is auto-sustained [40].
Inflammatory Markers and Prediction of Postoperative AF: Oxidative Stress Mediators
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Oxidative stress is a feature of the atrial myocardial remodeling and is believed to sustain AF [41]. The CPB with cardioplegic arrest determines myocardial oxidative stress (increased oxidized glutathione and lipid peroxidation [42]). Release of reactive oxygen metabolites occurs within the myocardium as part of the ischemia-reperfusion injury [43]. Patients developing new-onset AF have increased systemic and myocardial oxidative stress compared with patients who remained in sinus rhythm [44, 45]. Such a difference has been straightforwardly linked with a differential expression of genes involved in the regulation of systemic and myocardial redox balance. Variability in the genetic response to CPB may thus predispose certain individuals to postoperative AF. Acute inflammatory and oxidative stress and tissue cytokines directly decrease the upstroke velocity of the action potential by reducing the transmembrane sodium currents [46]. Conduction velocity was anisotropically decreased in right atrial appendages by the application of arachidonic acid (precursor of the inflammatory mediators’ leukotrienes, thromboxanes, and prostaglandins) [47].
Inflammatory Markers and Prediction of Postoperative AF: CRP and High-Sensitivity C-Reactive Protein High-sensitivity C-reactive protein is probably the most reliable and reproducible among the inflammatory markers [48]. In a study of CPB-related acute phase reaction it was reported that the peak incidence of AF on the second to third postoperative day coincides with the peak of blood CRP [49]. Nonetheless, the theory postulating a direct causative role of CRP in favoring atrial arrhythmias (ie, binding to cell membrane phosphorylcholine and transmembrane ion exchange disturbances, “arrhythmo-
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genic” properties of CRP) was not ultimately supported by data. CRP has different kinetics in various cardiac operations [50]. Raised preoperative CRP levels have been associated with the development of new AF after cardiac surgery [51]. Controlled studies have questioned the idea that acutely raised CRP levels in response to surgery and CPB may correlate with the likelihood of AF [31, 52, 53]. The CRP should be regarded as a generic marker of inflammation. When preoperatively raised, it may reflect the global likelihood of developing new-onset AF, as in nonoperated patients affected by cardiovascular disease. It may also correlate with the occurrence of postoperative AF, but there is no evidence that this is more than simple association. The CRP should not influence the decision on pharmacological strategies to prevent postoperative AF in cardiac surgical patients who were in sinus rhythm before the operation. With respect to the triggering of AF, the perioperative tendency toward systemic inflammation seems to be irrelevant compared with the inflammatory response elicited by surgery and CPB.
Studies Designed to Suppress an Inflammatory Response Therapeutic Implications: The “No-Pump” Approach Versus the “Glucocorticoid” Approach On the basis of the previous evidence, the reduction of the systemic inflammatory response is expected to be associated with less risk of new-onset AF. Two different methodological approaches have been pursued: offpump surgery and pharmacological modulation of the inflammatory response after on-pump operations. Coronary surgery without CPB is believed to elicit lesser systemic surge of inflammatory mediators than on-pump interventions [54]. Nonetheless, the clinical benefits of such a reduction in the systemic inflammatory response have not been conclusively demonstrated (Table 1). Several clinical series report no statistical association between off-pump surgery and less incidence of new-onset AF. However, such articles are often limited by their retrospective nature, or by incomplete adjustment for potential confounders, or for the coexistence of paroxysmal–persisting AF before surgery [55], or by the very limited sample size [56, 57]. Others evidenced different time distributions in the onset of AF in off-pump versus on-pump patients [58], which may indicate that different pathophysiologic means are at the root of AF genesis in these opposite circumstances. Because all studies showed at least a nonsignificant trend toward less AF incidence after off-pump surgery [59, 60, 61, 62], one should hypothesize that: (1) the advantage in terms of risk of AF after off-pump surgery, if present, may be little, and (2) insufficient statistical power and failure to adjust for confounding factors may be the reason for lack of statistical significance. Controlled randomized investigations of off-pump versus on-pump coronary surgery have indicated CPB plus cardioplegic arrest as the main predictors of new-onset
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Table 1. Studies Evaluating the Incidence of Atrial Fibrillation After On-Pump Versus Off-Pump Coronary Surgery Study Enc and colleagues [55] (2004) Siebert and colleagues [58] (2003) Scherer and colleagues [56] (2006) Murphy and colleagues [64] (2003) BHACAS 1—Ascione and colleagues [63] (2000) Boyd and colleagues [65] (1999) Van Belleghem and colleagues [66] (2003) Czerny and colleagues [59] (2001) BHACAS 2—Angelini and colleagues [60] (2002) Zamvar and colleagues [61] (2002) Légaré and colleagues [62] (2004)
Type of Study
No. of Patients
Mean Age
p Value*
Retrospective Retrospective Retrospective Prospective randomized Prospective randomized Retrospective Retrospective Prospective randomized Prospective randomized Prospective randomized Prospective randomized
670 1,067 72 200 200 90 458 80 201 60 300
60–61 59–61 57–66 NA 63 74 65–67 64–67 61–63 61–63 62–63
0.65 0.45 NS ⬍ 0.001 0.001 ⬍ 0.05 0.010 NS 0.017 0.12 0.20
* For difference in observed incidence of atrial fibrillation (AF) for on-pump versus off-pump.
AF [63, 64]. The reduction in the likelihood of AF after off-pump surgery may be more evident in the elderly surgical candidates [65] who are inherently more prone to AF, and in high-risk individuals with multiple preoperative comorbidities [66]. Finally, in a comprehensive review and meta-analysis of studies comparing off-pump versus on-pump surgery in the elderly [67], it was confirmed that the off-pump strategy is associated with a significantly decreased incidence of new-onset AF. This conclusion emerged despite the fact that 9 of 11 studies evidenced a nonsignificant tendency toward less incidence of postoperative AF in the off-pump cohorts. This is in keeping with the conclusions of the other two meta-analyses [68, 69]. Our meta-analysis of recent randomized controlled trials having the occurrence of postoperative AF as a study endpoint confirms these results, indicating a statistically significant advantage in terms of new-onset AF incidence if the pump is avoided (odds ratio, 0.427; 95% confidence interval, 0.306 to 0.597; total, 841 patients studied) (Fig 1). Should we presume that the importance of CPB-related inflammation in triggering AF is secondary compared with surgical stress alone? As an inherent limitation in the clinical series of on-pump coronary surgery, it must be considered that it is difficult to distinguish the weight of the systemic inflammatory reaction from that of atrial ischemia-reperfusion, cannulation, and incision in the genesis of AF. The degree of atrial myocardial inflammation is reported to increase with increasing the invasiveness of surgery; the extent of
atrial manipulation may vary and can influence the probability of AF [70]. Innovative CPB systems, which are more biocompatible and have been associated with a dramatic reduction in the entity of the inflammatory response [71, 72], should be investigated as potential tools to decrease the incidence of new-onset AF. Administration of methylprednisolone has resulted in decreased inhomogeneity of atrial conduction [35], and ultimately in less incidence or duration of AF in animal models of cardiac surgery [47]. In randomized studies, a single dose of dexamethasone (0.6 mg/kg or 1 g) at induction of anesthesia, could achieve a statistically significant lower rate of new-onset AF [73]. Lower dexamethasone doses did not prove beneficial in this respect. A critical issue is presumably the drug dose load, the number of doses, and the time of administration [74]. Despite modest statistical power, a combination of methylprednisolone (1 g) before surgery plus dexamethasone (4 mg every 6 hours) thereafter, significantly reduced the incidence of new-onset AF in a randomized investigation. A large, multicenter, randomized trial of these studies confirmed the efficacy of glucocorticoid treatment to reduce the cases of postoperative AF [75, 76]. Drug administration protocols including the first 48 to 72 postoperative hours, in which the systemic inflammatory reaction to CPB is more evident, are thus reported to obtain better results. The previous data represent an indirect criterion substantiating the pathogenetic link between inflammation and new-onset AF. Aside from Fig 1. Intervention effect of off-pump strategy versus on-pump technique for coronary surgery on incidence of postoperative atrial fibrillation (AF) in prospective randomized trials (forest plot). Error bars indicate 95% confidence intervals (CIs).
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NS ⫽ nonsignificant.
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Table 2. Studies Evaluating the Effects of Statin Treatment on the Incidence of Postoperative Atrial Fibrillation Study Patti and colleagues [89] (2006) Marin and colleagues [86] (2006) Ozaydin and colleagues [87] (2007) Mariscalco and colleagues [88] (2007) Lertsburapa and colleagues [84] (2008) Kourliouros and colleagues [90] (2008)
Type of Study
No. of Patients
p Value*
Prospective randomized Prospective nonrandomized Prospective nonrandomized Retrospective Prospective randomized Retrospective
200 234 362 405 555 623
0.003 0.024 0.03 0.021 0.035 ⬍ 0.001
* For difference in observed incidence of atrial fibrillation for statin-treated versus non-statin-treated group.
this, the question remains open as to whether the use of glucocorticoids to prevent AF in cardiac surgical patients is clinically worthwhile. No significant increase in major morbidity has been reported in most studies [77]; however, minor postoperative morbidity may rise. Such issues deserve investigation in view of the larger application. Thus, both the “no-pump” approach and the “glucocorticoid” approach present inherent limitations. The CPB can not be avoided in the vast majority of cardiac operations. Off-pump coronary artery bypass grafting remains a challenging procedure in multivessel disease, and its applicability is limited by surgeon-dependent factors (ie, specific training required with a long learning curve) and by nonsurgeon-dependent factors (ie, the possibility of hemodynamic instability and revascularization required for obtuse marginal and posterolateral branches). In addition, the advantages of off-pump coronary artery bypass grafting in terms of less AF incidence in the real world are probably lower than theoretically expected. Steroids are reportedly efficacious, but significant doses are required and perioperative morbidity may increase. Reports on other anti-inflammatory agents are scattered and evidence in humans are lacking. REVIEWS
Statins, Inflammatory Status, and AF The 3-hydroxy-3-methyl-glutaryl coenzyme-A reductase inhibitors, known as statins, were reported to achieve a number of pharmacological effects beyond their primary lipid-lowering action, including anti-inflammatory properties (pleiotropic effects) [78]. Simvastatin, pravastatin, and atorvastatin reduced the high-sensitivity C-reactive protein levels, but not the IL-6 levels, during primary prevention in dyslipidemic patients [79]. Statins improve nitric oxide-dependent endothelial function [80] and have anti-oxidant properties [81], as well as antiproliferative effects, although such effects are still to be demonFig 2. Intervention effect of preoperative statin treatment versus controls on incidence of atrial fibrillation (AF) after cardiac surgery in prospective randomized trials (forest plot). Error bars indicate 95% confidence intervals (CIs).
strated in the acute setting of inflammatory reaction to CPB. Patients with lone AF who had successful cardioversion were more likely to maintain sinus rhythm at follow-up if treated with statins [82]. The use of statins in patients with stable coronary artery disease is protective against development of new AF [83]. Preoperative statin treatment reduced the postoperative incidence of AF in a cohort of patients subjected to thoracic off-pump noncardiac surgery [84]. Such effect was independent of the systemic release of inflammatory markers (CRP/IL-6), thus suggesting that the mechanisms through which statins exert their anti-arrhythmic properties lie at the tissue level. Statins may reduce the incidence of newonset AF, even in patients administered with prophylactic beta-blockers and amiodarone [85]. Atorvastatin decreased the release of inflammatory markers and neutrophil activation after CPB [85]. Statin treatment initiated before on-pump surgery was then reported as protective against the development of AF [86 – 88]. This observation was confirmed in a randomized trial [89]. In this study, the pre-treatment (atorvastatin, 40 mg per day, administered irrespective of the cholesterol level) was standardized to a 7-day preoperative duration, and it was a multivariable predictor of reduced risk of new-onset AF. The efficacy of statins in preventing the onset of AF may be dose-dependent [90]. Two controlled randomized studies focused on the effects of statin pre-treatment on the occurrence of postoperative AF were included in the meta-analysis (total, 755 patients studied) (Table 2). Although the small number of available studies is potentially a study limitation, results indicate that statin pre-treatment is effective in preventing postoperative AF (odds ratio, 0.572; 95% confidence interval, 0.421 to 0.777) (Fig 2). Statins may be realistically applied to this purpose in daily clinical practice. However, an ongoing investigation is required,
REVIEW ANSELMI ET AL POSTOPERATIVE INFLAMMATION AND ATRIAL FIBRILLATION
as the small number of studies available up to now represents a limitation of the present analysis. Statins have not been demonstrated to have any direct anti-arrhythmic effect by pharmacological activity on ion channels and transmembrane currents. Conversely, the reduction of new-onset AF associated with statins may be ascribed to the modulation of various pathophysiologic mechanisms which favor the onset of AF. The systemic and myocardial inflammation and the oxidative balance are reasonable among such mechanisms.
Comment The concept that inflammation is a causative pathophysiologic element of postoperative AF is supported by recent literature. Such a link displays different features in nonoperated patients with cardiovascular disease versus patients undergoing cardiac surgery. In the latter case, the acute systemic inflammatory reaction due to CPB and generalized surgical trauma is a main determinant of new-onset AF, although it is difficult to quantify its relative importance in comparison with other factors, such as direct surgical trauma of the atria (ie, incision, cannulation, and so forth). Nonetheless, the modulation of inflammation will probably represent a major therapeutic goal in the short term and a promising pathway. Among the strategies attempted, statins currently represent the most reasonable pathway in the clinical treatment-outcome balance to reduce the incidence of AF after cardiac surgery. Further investigations to conclusively demonstrate their efficacy are warranted.
References 1. Hogue CW, Creswell LL, Gutterman DD, Fleisher LA. Epidemiology, mechanisms and risks: American college of chest physicians guidelines for the prevention and management of postoperative atrial fibrillation. Chest 2005;128:9 –16. 2. Zaman AG, Archbold RA, Helft G, Paul EA, Curzen NP, Mills PG. Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification. Circulation 2000;101:1403– 8. 3. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004;291:1720 –9. 4. Kalavrouziotis D, Buth KJ, Ali IS. The impact of new-onset atrial fibrillation on in-hospital mortality following cardiac surgery. Chest 2007;131:833–9. 5. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061–73. 6. Tamis JE, Steinberg JS. Atrial fibrillation independently prolongs hospital stay after coronary artery bypass surgery. Clin Cardiol 2000;33:155–9. 7. Tamis-Holland JE, Kowalski M, Rill V, Firoozi K, Steinberg JS. Patterns of atrial fibrillation after coronary artery bypass surgery. Ann Noninvasive Electrocardiol 2006;11:139 – 44. 8. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 1996;94:390 –7. 9. Magee MJ, Herbert MA, Dewey TM, et al. Atrial fibrillation after coronary artery bypass surgery: development of a predictive risk algorithm. Ann Thorac Surg 2007;83:1707–12. 10. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003; 108:3006 –10.
331
11. Gaudino M, Andreotti F, Zamparelli R, et al. The -174G/C inetrleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation 2003; 108:195–9. 12. 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 –91. 13. Hatzinikolau-Kotsakou E, Tziakas D, Hotidis A, Stakos D, Floros D, Mavridis A. Relation of C-reactive protein to the first onset and the recurrence rate in lone atrial fibrillation. Am J Cardiol 2006;97:659 – 61. 14. Watanabe E, Arakawa T, Uchiyama T, Kodama I, Hishida H. High-sensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion. Int J Cardiol 2006;108:346 –53. 15. Acevedo M, Corbalàn R, Braun S, Pereira J, Navarrete C, Gonzalez I. C-reactive protein and atrial fibrillation: evidence for the presence of inflammation in the perpetuation of the arrhythmia. Int J Cardiol 2006;108:326 –31. 16. Tveit A, Seljeflot I, Grundvold I, Abdelnoor M, Smith P, Arnesen H. Effect of candesartan and various inflammatory markers on maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation. Am J Cardiol 2007;1999: 1544 – 8. 17. Gedikli O, Dogan A, Altuntas I, Altinbas A, Ozaydin M, Akturk O. Inflammatory markers according to types of atrial fibrillation. Int J Cardiol 2007;120:193–7. 18. Conway D, Biggins P, Hughes E, Lip G. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol 2004;43: 2075– 82. 19. Korantzopoulos P, Kolettis TM, Kountouris E, et al. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. Int J Cardiol 2005; 102:321– 6. 20. Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001;104:174 – 80. 21. Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit 2003;9: RA225–9. 22. Cosgrave J, Foley JB, Flavin R, et al. Preoperative atrial histological changes are not associated with postoperative atrial fibrillation. Cardiovasc Pathol 2006;15:213–7. 23. Kawahito K, Kobayashi E, Ohmori M, et al. Enhanced responsiveness of circulatory neutrophils after cardiopulmonary bypass: increased aggregability and superoxide production capacity. Artif Organs 2000;24:37– 42. 24. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophyisiology and treatment: an update. Eur J Cardiothorac Surg 2002;21:232– 44. 25. Zahler S, Massoudy P, Hartl H, Hahnel C, Meinser H, Becker BF. Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass. Cardiovasc Res 1999;41:722–30. 26. te Velthuis H, Janse PG, Oudemans-van Straaten HM, Sturk A, Eijsman L, Wildevuur CR. Myocardial performance in elderly patients after cardiopulmonary bypass is suppressed by tumor necrosis factor. J Thorac Cardiovasc Surg 1995;110: 1663–9. 27. Grunenfelder J, Zund G, Schoeberlein A, et al. Modified ultrafiltration lowers adhesion molecules and cytokine levels after cardiopulmonary bypass without clinical relevance in adults. Eur J Cardiothorac Surg 2000;17:77– 83. 28. Toprak V, Sirin BH, Tok D, Ozbilgin K, Saribulbul O. The effect of cardiopulmonary bypass on the expression of inducible nitric oxide synthase, endothelial nitric oxide synthase, and vascular endothelial growth factor in the internal mammary artery. J Cardiothorac Vasc Anesth 2006;20:63–7.
REVIEWS
Ann Thorac Surg 2009;88:326 –33
332
REVIEW ANSELMI ET AL POSTOPERATIVE INFLAMMATION AND ATRIAL FIBRILLATION
REVIEWS
29. Abdelhadi RH, Gurm HS, Van Wagoner D, Chung MK. Relation of an exaggerated rise in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively. Am J Cardiol 2004;93: 1176 – 8. 30. Lamm G, Auer J, Weber T, Berent R, Nq C, Eber B. Postoperative white blood cell count predicts atrial fibrillation after cardiac surgery. J Cardiothorac Vasc Anesth 2006; 20:51– 6. 31. Fontes ML, Mathew JP, Rinder HM, Zelterman D, Smith BR, Rinder CS; Multicenter study of perioperative ischemia (McSPI) research group. Atrial fibrillation after cardiac surgery/cardiopulmonary bypass is associated with monocyte activation. Anesth Analg 2005;101:17–23. 32. Koch CG, Li L, Van Wagoner D, Duncan AI, Gillinov AM, Blackstone EH. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 2006;82:1747–57. 33. Fransen E, Maessen J, Dentener M, Senden N, Buurman W. Impact of blood transfusions of inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999;116: 1233–9. 34. Hoffman BF, Feinmark SJ, Guo SD. Electrophysiologic effects of interactions between activated canine neutrophils and cardiac myocytes. J Cardiovasc Electrophysiol 1997;8:679 – 87. 35. Ishii Y, Schuessler RB, Gaynor SL, et al. Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 2005;111:2881– 8. 36. Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando: Grune & Stratton Inc 1985:265–75. 37. Dupont E, Ko YS, Rothery S, et al. The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation 2001;103:842–9. 38. Ishida K, Kimura F, Imamaki M, et al. Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 2006;29: 501–5. 39. Fernandez-Cobo M, Gingalewski C, Drujan D, De Maio A. Downergulation of connexin 43 gene expression in rat heart during inflammation. The role of tumor necrosis factor. Cytokine 1999;11:216 –24. 40. Anselmi A, Abbate A, Girola F, et al. Myocardial ischemia, stunning, inflammation and apoptosis during cardiac surgery: a review of evidence. Eur J Cardiothorac Surg 2004;25: 304 –11. 41. Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and the left atrial appendage: role of NADPH and xanthine oxidases. Circulation 2005;112:1266 –73. 42. De Vecchi E, Pala MG, Di Credico G, et al. Relation between left ventricular function and oxidative stress in patients undergoing bypass surgery. Heart 1998;79:242–7. 43. Wan S, Yim AP, Wong CK, et al. Expression of FHL2 and cytokine messenger RNAs in human myocardium after cardiopulmonary bypass. Int J Cardiol 2002;86:265–72. 44. Ramlawi B, Out H, Mieno S. Oxidative stress and atrial fibrillation after cardiac surgery: a case-control study. Ann Thorac Surg 2007;84:1166 –73. 45. Carnes CA, Chung MK, Nakayama T, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001;89:E32– 8. 46. Wang GK, Wang SY. Modifications of human cardiac sodium channel gating by UVA light. J Membr Biol 2002;189: 153– 65. 47. Tselentakis EV, Woodford E, Chandy J, Gaudette GR, Saltman AE. Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. J Surg Res 2006;135:68 –75.
Ann Thorac Surg 2009;88:326 –33
48. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation: part 1. Circulation 2003;108:1917–23. 49. 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;96:3542– 8. 50. Gaudino M, Nasso G, Andreotti F, et al. Preoperative C-reactive protein level and outcome following coronary surgery. Eur J Cardiothorac Surg 2002;22:521– 6. 51. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk factor for atrial fibrillation after myocardial revascularization. Ann Thorac Surg 2005;79:1530 –35. 52. 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. 53. Ahlsson AJ, Bodin L, Lundblad OH, Englund AG. Postoperative atrial fibrillation is not correlated to C-reactive protein. Ann Thorac Surg 2007;83:1332–7. 54. Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999;68:52– 6. 55. Enc Y, Ketenci B, Ozsoy D, et al. Atrial fibrillation after surgical revascularization: is there any difference between on-pump and off-pump? Eur J Cardiothorac Surg 2004;26: 1129 –33. 56. Scherer M, Sirat AS, Dogan S, Aybeck T, Moritz A, WimmerGreinecker G. Does totally endoscopic access for off-pump cardiac surgery influence the incidence of postoperative atrial fibrillation in coronary artery bypass grafting? A preliminary report. Cardiovasc Eng 2006;6:118 –21. 57. Abreu JE, Reilly J, Salzano RP, Khachane VB, Jekel JF, Clyne CA. Comparison of frequencies of atrial fibrillation after coronary artery bypass grafting with and without the use of cardiopulmonary bypass. Am J Cardiol 1999;83:775– 6. 58. Siebert J, Lewicki L, Mlodnicki M, et al. Atrial fibrillation after conventional and off-pump coronary artery bypass grafting: two opposite trends in timing of atrial fibrillation occurrence? Med Sci Monit 2003;9:CR137– 41. 59. Czerny M, Baumer H, Kilo J, et al. Complete revascularization in coronary artery bypass grafting with and without cardiopulmonary bypass. Ann Thorac Surg 2001;71:165–9. 60. Angelini DG, Taylor FC, Reeves BC, Ascione R. Early and midterm outcome of after off-pump and on-pump surgery in beating heart against cardioplegic arrest studies (BHACAS 1 and 2): a pooled analysis of two randomized controlled trials. Lancet 2002;359:1194 –9. 61. Zamvar V, Williams D, Hall J, et al. Assessment of neurocognitive impairment after off-pump and on-pump technique for coronary artery bypass graft surgery: a prospective randomized controlled trial. BMJ 2002;325:1268. 62. Légaré JF, Buth KJ, King S et al. Coronary bypass surgery performed off-pump may not result in lower in-hospital morbidity than coronary artery bypass grafting performed on-pump. Circulation 2004;109:887–92. 63. Ascione R, Caputo M, Calori G, Lloyd CT, Underwood MJ, Angelini GD. Predictor of atrial fibrillation after conventional and beating heart coronary surgery: a prospective, randomized study. Circulation 2000;102:1530 –5. 64. Murphy GJ, Ascione R, Caputo M, Angelini GD. Operative factors that contribute to postoperative atrial fibrillation: insights from a prospective randomized trial. Card Electrophysiol Rev 2003;7:136 –9. 65. Boyd WD, Desai ND, Del Rizzo DF, Novick RJ, McKenzie FN, Menkis AH. Off-pump surgery decreases postoperative complications and resource utilization in the elderly. Ann Thorac Surg 1999;68:1490 –3. 66. Van Belleghem Y, Caes F, Van Overbeke H, Moerman A, Van Nooten G. Off-pump coronary surgery: surgical strategy for the high-risk patient. Cardiovasc Surg 2003;11:75–9.
REVIEW ANSELMI ET AL POSTOPERATIVE INFLAMMATION AND ATRIAL FIBRILLATION
67. Panesar SS, Athanasiou T, Nair S, et al. Early outcomes in the elderly: a meta-analysis of 4921 patients undergoing coronary artery bypass grafting— comparison between offpump and on-pump techniques. Heart 2006;92:1808 –16. 68. Reston JT, Tregear SJ, Turkelson CM. Meta-analysis of short-term and mid-term outcomes following off-pump coronary artery bypass grafting. Ann Thorac Surg 2003;76: 1510 –5. 69. Cheng DC, Bainbridge D, Martin JE, Novick RJ. The evidence-based perioperative clinical outcomes research group. Does off-pump coronary artery bypass reduce mortality, morbidity and resource utilization when compared with conventional coronary artery bypass? A meta-analysis of randomized trials. Anesthesiology 2005;102:188 –203. 70. Stamou SC, Dangas G, Hill PC. Atrial fibrillation after beating heart surgery. Am J Cardiol 2000;86:64 –7. 71. Fromes Y, Gaillard D, Ponzio O, et al. Reduction of the inflammatory response following coronary bypass grafting with total minimal extracorporeal circulation. Eur J Cardiothorac Surg 2002;22:527–33. 72. Pransongsukarn K, Abel JG, Jamieson WR, et al. The effects of steroids on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting surgery: a prospective randomized trial. J Thorac Cardiovasc Surg 2005;130: 93– 8. 73. Yared JP, Starr NJ, Torres FK, et al. Effects of a single dose, postinduction dexamethasone on recovery after cardiac surgery. Ann Thorac Surg 2000;69:1420 – 4. 74. Yared JP, Bakri MH, Erzurum SC, et al. Effect of dexamethasone on atrial fibrillation after cardiac surgery: prospective, randomized, double-blind, placebo-controlled trial. J Cardiothorac Vasc Anesth 2007;21:68 –75. 75. Rubens FD, Nathan H, Labow R, et al. Effects of methylprednisolone and a biocompatible copolymer circuit on blood activation during cardiopulmonary bypass. Ann Thorac Surg 2005;79:655– 65. 76. Patel AA, White CM, Shah SA, Dale KM, Kluger J, Coleman CI. The relationship between statin use and atrial fibrillation. Curr Med Res Opin 2007;23:1177– 85. 77. Halvorsen P, Raeder J, White PF, et al. The effect of dexamethasone on side effects after coronary revascularization procedures. Anesth Analg 2003;96:1578 – 83. 78. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Deveraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase
79. 80. 81. 82.
83. 84.
85.
86. 87. 88.
89.
90.
333
inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933–5. Halonen J, Halonen P, Jarvinen O, et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA 2007;297:1526 –7. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129 –35. Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108:426 –31. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003; 92:1343–5. Chello M, Patti G, Candura D, et al. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery. Crit Care Med 2006;34:660 –7. Lertsburapa K, White CM, Kluger J, Faheem O, Hammond J, Coleman CI. Preoperative statins for the prevention of atrial fibrillation after cardiothoracic surgery. J Thorac Cardiovasc Surg 2008;135:405–11. Amar D, Zhang H, Heerdt P, Park B, Fleisher M, Thaler H. Statin use is associated with a reduction in atrial fibrillation after noncardiac thoracic surgery independent of C-reactive protein. Chest 2005;128:3421–7. Marin F, Pascual DA, Roldan V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 2006;97:55– 60. Ozaydin M, Dogan A, Varol E, et al. Statin use before bypass surgery decreases the incidence and shortens the duration of postoperative atrial fibrillation. Cardiology 2007;107:117–21. Mariscalco G, Lorusso R, Klersy C, et al. Observational study on the beneficial effect of preoperative statins in reducing atrial fibrillation after coronary surgery. Ann Thorac Surg 2007;84:1158 – 64. Patti G, Chello M, Candura D, et al. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (atorvastatin for reduction of myocardial dysrythmia after cardiac surgery) study. Circulation 2006;114:1455– 61. Kourliouros A, De Souza A, Roberts N, et al. Dose-related effect of statins on atrial fibrillation after cardiac surgery. Ann Thorac Surg 2008;85:1515–20. REVIEWS
Ann Thorac Surg 2009;88:326 –33