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Ann Thorac Surg 2007;83:1332-1337
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Postoperative Atrial Fibrillation is Not Correlated to C-Reactive Protein

Anders J. Ahlsson, MDa,*, Lennart Bodin, PhDb, Olof H. Lundblad, MDa, Anders G. Englund, MD, PhDc

a Departments of Cardiothoracic Surgery and Anesthesiology, Örebro University Hospital, Örebro, Sweden
b Departments of Statistics and Epidemiology, Örebro University Hospital, Örebro, Sweden
c Department of Cardiology, Örebro University Hospital, Örebro, Sweden

Accepted for publication November 16, 2006.

* Address correspondence to Dr Ahlsson, Department of Cardiothoracic Surgery and Anesthesiology, Örebro University Hospital, 701 85 Örebro, Sweden (Email: anders.ahlsson{at}orebroll.se).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The peak incidence of postoperative atrial fibrillation (AF) occurs around the second postoperative day, a time at which serum inflammatory markers are elevated. The aim of this study was to investigate differences between patients with and without postoperative AF with special regard to C-reactive protein (CRP) serum levels.

Methods: The study cohort included all heart surgery patients who had sinus rhythm preoperatively, survived postoperative day 3, and were operated on between July 1, 2004, and June 30, 2005 (n = 524). Any episode of AF during the first 7 postoperative days defined the patient as belonging to the postoperative AF group. Creatine kinase–myocardial band (CK-MB) was measured at postoperative day 1, and CRP was measured preoperatively and at postoperative day 3. Risk factors for postoperative AF were determined using bivariate and multivariate regression analysis.

Results: Of 524 patients, 182 had at least one episode of AF (34.7%). Preoperative and postoperative CRP concentrations did not differ between the groups (postoperative CRP 175.4 ± 64.4 versus 175.3 ± 60.1 mg/L respectively, p = 0.99). Atrial fibrillation patients were significantly older (p < 0.001) and had higher CK-MB levels (33.6 ± 53.1 µg/L versus 22.5 ± 26.7 µg/L, respectively, p = 0.009). The odds ratio for postoperative AF with postoperative CK-MB greater than 70 µg/L was 3.5 (confidence interval: 1.4 to 8.6).

Conclusions: Postoperative AF has no correlation to the inflammatory marker CRP in heart surgery patients. Ischemic myocardial injury might predispose for postoperative AF.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
New etiologic mechanisms of atrial fibrillation (AF) have been proposed in recent years. In particular, there is increasing evidence of a link between AF and inflammation. In histological studies, atrial biopsies from patients with lone AF have shown a high degree of inflammatory infiltrates compared with controls [1]. In a case-control study, patients with AF had significantly elevated C-reactive protein (CRP) levels compared with controls, and the elevation was greatest in patients with more persistent AF [2]. The C-reactive protein, named for its capacity to precipitate C-polysaccharide of Streptococcus pneumoniae, is an acute-phase protein and one of the most sensitive systemic markers of inflammation. Its precise role in the inflammation process is unclear; however, it binds to phosphocholine and is potentially able to recognize damaged cell membranes. It has been proposed that the resulting effect on sodium and calcium exchange could induce arrhythmia [3, 4].

Open heart surgery leads to a systemic inflammatory response marked by increased levels of cytokines like interleukin-6, complements, and CRP [5]. The levels of CRP usually peak at day 3 postoperatively [6]. The incidence of postoperative AF varies between 25% and 40% in different studies with a peak incidence at days 2 to 3 postoperatively [7]. Thus, the timing of postoperative AF seems to coincide with the maximum CRP levels.

Among cardiac surgery patients, the incidence of postoperative AF has been shown to correlate with white blood cell counts, postoperative levels of CRP-complement complexes, and preoperative CRP levels [5, 8, 9]. It is not known, however, whether the degree of postoperative inflammation as measured by CRP levels correlates to the incidence of AF. The aim of this study was therefore to investigate predictors of postoperative AF in a large cohort of heart surgery patients, with special emphasis on preoperative and postoperative CRP levels.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Cohort
The study sample was taken from among the 575 patients who underwent open heart surgery at the Department of Thoracic and Cardiovascular Surgery, Örebro University Hospital, between July 1, 2004, and June 30, 2005 (Fig 1). Of these 575 patients, 51 were excluded from the study: 3 patients died before postoperative day 3, 10 patients were excluded owing to having undergone miscellaneous surgery that was hard to classify (rewarming, atrial myxoma, postinfarction ventricular septal defect, acute pulmonary embolism, and so on), and 38 patients (6.6%) were excluded for having had preoperative AF. The remaining 524 patients formed the study cohort. The study was approved by the Regional Ethical Committee, Uppsala, Sweden, on January 25, 2006, and individual informed consent was waived.


Figure 1
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  		Fig 1. Study design. (ASD = atrial septal defect; VSD = ventricular septal defect.)

 
Data Collection
Patient background data as well as perioperative and postoperative variables were prospectively registered in a clinical database. The study database, from which analyses were made, comprised information from this database together with retrospectively collected data from patient records and laboratory data. Among the data registered were patient characteristics (age, sex, body mass index), concomitant diseases, and EuroSCORE (European System for Cardiac Operative Risk Evaluation) and Higgins risk scores. Ejection fraction (EF) was classified using echocardiography or left ventricular angiograms as "normal" (approximately 65% to 80%), "slightly reduced" (approximately 50% to 65%), "moderately reduced" (approximately 30% to 50%), or "markedly reduced" (less than 30%). Perioperative and postoperative data included surgical time, cardiopulmonary bypass time (CPB), and aortic clamp time (all in minutes). Duration of intubation and time in intensive care were also registered. Among the complications registered were transient or permanent focal neurologic deficit of any kind, defined collectively as "stroke," and hospital mortality.

Concentration of CRP in serum, expressed as mg/L, was measured twice: on the morning of the day before surgery and on the morning of the third postoperative day. Creatinine in serum, expressed as µmol/L, was obtained on the morning after surgery and on the third postoperative day. The CRP and creatinine levels were determined using dry chemistry methods on a Vitros 250 or Vitros 950 instrument (Ortho-Clinical Diagnostics, Rochester, NY). The CRP method was an enzyme immunoassay, and the total coefficients of variation (CVs) were 8.4% and 7.5% at 24 mg/L and 70 mg/L, respectively. The creatinine method was based on the enzyme creatinine amidohydrolase, and the total CVs were 1.4% and 1.2% at 83 µmol/L and 510 µmol/L, respectively.

Creatinine kinase-myocardial band (CK-MB) in serum, expressed as µg/L, was measured on the morning after the surgery (typically 18 hours after wound closure). The CK-MB value was determined by an electrochemiluminescence immunoassay on an Elecsys 2010 instrument (Roche Diagnostics, Mannheim, Germany). Total CVs were 7.7% and 3.4% at 2.6 µg/L and 48.7 µg/L, respectively.

Extracorporeal Circulation and Cardioplegia
The extracorporeal circuit consisted of an open venous reservoir (Sorin, Mirandola, Italy) primed with 2,000 mL Ringer’s acetate, a roller pump, a hollow fiber oxygenator with integrated heat exchanger (Sorin), and a polyvinyl tubing system.

Systemic heparinization (300 U/kg) was used to keep the activated clotting time greater than 480 s. A nonpulsatile roller pump was used, and flow was kept at 2.4 L · min–1 · m–2. Nasopharyngeal temperature was routinely allowed to drift to 34°C during the procedure. For myocardial protection, patients received a bolus dose of 1,000 mL high potassium cold blood cardioplegia (8°C to 10°C), followed by intermittent infusions of 300 mL every 20 minutes of aortic clamping. Cardioplegia was administered in the aortic root despite in-valve procedures, where also retrograde administration through cannulation of the coronary sinus was used. If electrical activity was registered during aortic clamping, cardioplegia was readministered. For off-pump surgery, activated clotting time was kept longer than 300 s.

Atrial Fibrillation Management
No specific AF prophylaxis was used during the study. Routine treatment of postoperative AF included administration of sotalol or amiodarone and anticoagulation with low molecular weight heparins.

All patients were monitored by continuous five-lead telemetry (Teleguard, GE Healthcare, Waukesha, WI) until postoperative day 4. From day 5 until dismissal, pulse was checked at least twice daily, and telemetry was reinstituted if arrhythmia was detected clinically. A standard 12-lead electrocardiogram was routinely obtained on days 1 and 5.

Episodes of arrhythmia were captured by an automatic alarm function and were printed out and recorded. The telemetry recordings were also routinely assessed three times daily and at discharge by the heart surgeon responsible for the case. The onset and duration of AF were recorded as well as the presence of AF at discharge.

A patient was classified as belonging to the postoperative AF group if they had been in sinus rhythm preoperatively, and then registered any episode of AF lasting more than 1 minute during the first 7 postoperative days.

Statistical Analysis
Categorical variables were compared using {chi}2 tests, while continuous variables were compared using either Student’s t test for independent samples or the nonparametric Mann-Whitney U test, depending on scale and measurement type. When appropriate, skewed distributions were transformed to logarithms before application of the parametric tests. Predictors of postoperative AF were identified using first bivariate and then multiple logistic regression analysis. A series of variables was screened using bivariate analysis, and those attaining a p value of 0.10 or less were entered into a multiple logistic regression model. The cofactors remaining in the model were checked for linearity, and if nonlinearity was the case, transformation or categorization was used. The modeling strategy was based on Katz [10]. Statistical analysis was performed using SPSS software, version 13 (SPSS, Chicago, Illinois).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Baseline data are shown in Table 1. The postoperative AF patients were older (p < 0.001), had more often preoperative ß-blockade (p = 0.003) and scored significantly higher on both Higgins and EuroSCORE indexes (p < 0.001).


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  		Table 1 Patient Characteristics
 
The median onset of postoperative AF was at day 2, with a median duration of 2 days (interquartile range, 1 to 4; Fig 2). The type of surgery performed is shown in Table 2. There were significant differences in frequency of AF between the types of surgery, with the highest frequency (60.6%) among patients undergoing aortic valve replacement and revascularization.


Figure 2
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  		Fig 2. Onset of atrial fibrillation (AF).

 

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  		Table 2 Type of Surgery in Study Cohort (n = 524)
 
The CRP concentration did not differ between patients with postoperative AF and patients without AF, either preoperatively or at the third postoperative day. In fact, the CRP concentrations in both groups were very similar (Table 3).


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  		Table 3 Operative Data and Postoperative Results
 
Postoperative CK-MB levels were higher in the AF group (p = 0.009), as was the peak value of postoperative creatinine (p < .001). The respirator times were longer in the AF group, as were the surgical time, the cross-clamp time, and the CPB time. The hospital mortality in the cohort was limited to patients in the AF group (p = 0.002).

The logistic regression analysis is summarized in Table 4. Preoperative CRP and postoperative day 3 CRP showed no significant relations to postoperative AF in bivariate analysis. Age, postoperative CK-MB value greater than 70 µg/L, prolonged respirator time, and time in operation room were all significant predictors of postoperative AF; and as all these variables showed a nonlinear relationship, they were categorized. In the multivariate analysis, age remained a significant predictor of postoperative AF with an odds ratio of 4.39 (2.41 to 8.00) in the age group 68 to 76 years and 3.58 (1.89 to 6.78) in the age group more than 76 years old compared with the age group younger than 61 years. Patients with postoperative CK-MB concentration greater than 70 µg/L had an odds ratio for developing AF of 3.04 (1.13 to 8.18) compared with patients with concentrations below 70 µg/L. The multivariate analysis model in Table 4 had a total misclassification rate of 30.2%, with a specificity and sensitivity for AF of 91.2% and 28.5%, respectively. This finding means that the majority of the postoperative AF patients could not be detected using the variables in the model.


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  		Table 4 Postoperative Atrial Fibrillation by Logistic Regression Analysis
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The most important finding of the present study was that there was no correlation between preoperative or postoperative concentrations of CRP and the development of postoperative AF.

The theory behind the arrythmogenic properties of CRP is that it binds to phosphocholine in damaged cell membranes; it has been postulated that this might contribute to membrane dysfunction and subsequent ion exchange disturbances and arrhythmia [3–5]. The inflammatory component in AF genesis is supported by several clinical and experimental studies. Patients with paroxysmal or permanent AF have been found to have elevated CRP levels compared with controls, and elevated CRP has been shown to act as a predictor for future episodes of AF [2, 4, 11, 12]. In both patients and animals, atrial biopsies from fibrillating hearts have shown a high degree of inflammatory infiltrates compared with controls [1, 13]. Polymorphism in the interleukin-6 gene has been shown to correlate with the incidence of postoperative AF [14] as well as postoperative rise in polymorphonuclear leucocytes and monocytes [15].

The relation between CRP and postoperative AF has been studied with conflicting results. Preoperative CRP greater than 3.0 mg/L was correlated to postoperative AF in one study [9], whereas three other studies found no associations between preoperative CRP levels and AF [15–17]. Postoperative CRP–complement 4 D complexes at day 2 were associated with AF [5] in one study, but two other studies found no correlations between postoperative CRP and AF [14, 16].

As this is the largest study so far, having the highest power to study the correlations between preoperative or postoperative CRP levels and postoperative AF, we might conclude that the absence of correlation is a true negative finding. One question that has been raised is whether CRP acts only as a marker or as a true etiologic substance that induces membrane dysfunction. The results of this study suggest that CRP is only a marker of inflammatory activity. Also, the previously known connection between AF and elevated CRP levels, either as predictor or marker, has been demonstrated in patients with permanent or paroxysmal fibrillation of some duration [2, 4, 11, 12]. A possible explanation for this is that in patients with long-lasting AF, this state generates an inflammatory response—in other words, atrial fibrillation is the hen rather than the egg. Finally, CRP levels were of a milder magnitude, with a twofold increase compared with the approximately 30-fold increase seen in the postoperative setting.

It is of interest to note that patients with a CK-MB value greater than 70 µg/L had a significantly higher risk of developing AF. This finding indicates a possible myocardial injury mechanism that promotes AF development. To our knowledge, postoperative myocardial enzyme levels have not been correlated to postoperative AF. This finding warrants further investigation, especially with potentially more sensitive markers of myocardial injury like troponins.

Age is a well-known predictor for AF, with various studies having found an increasing risk from 65 to 75 years of age [7, 18, 19]. In this material, we found a nonlinear relationship, with the highest risk among ages greater than 68 years.

In conclusion, this study showed no correlation between preoperative or postoperative CRP concentrations and the development of postoperative AF. Important risk factors for postoperative AF were age and CK-MB values greater than 70 µg/L.

Limitations
The incidence and timing of postoperative AF in our study are in concordance with earlier studies [7]. Even though the most sensitive method of AF registration was used, namely, continuous telemetry, it is still observer-dependent, and we cannot preclude higher prevalence in reality. Because postoperative CRP concentration was only measured once at day 3, we cannot exclude the possibility of a correlation between CRP and postoperative AF at some other time in the postoperative period. And because the only inflammatory variable studied was CRP, this study does not exclude a link between AF and inflammation. The correlation between postoperative AF and CK-MB levels must also be interpreted with caution, as the number of patients is comparatively small in the high concentration group.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was funded by the Research Committee of Örebro University Hospital. We thank Clinical Research Support, Örebro University Hospital, for valuable help in data collection.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation Circulation 1997;96:1180-1184.[Abstract/Free Full Text]
  2. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation Circulation 2001;104:2886-2891.[Abstract/Free Full Text]
  3. Dernellis J, Panaretou M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation Eur Heart J 2004;25:1100-1107.[Abstract/Free Full Text]
  4. Engelmann MD, Svendsen JH. Inflammation in the genesis and perpetuation of atrial fibrillation Eur Heart J 2005;26:2083-2092.[Abstract/Free Full Text]
  5. Bruins P, te Velthuis H, Yazdanbakhsh AP, et al. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia Circulation 1997;96:3542-3548.[Abstract/Free Full Text]
  6. Gaudino M, Nasso G, Andreotti F, et al. Preoperative C-reactive protein level and outcome following coronary surgery Eur J Cardiothorac Surg 2002;22:521-526.[Abstract/Free Full Text]
  7. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgeryCurrent trends and impact on hospital resources. Circulation 1996;94:390-397.[Abstract/Free Full Text]
  8. Abdelhadi RH, Chung MK, Van Wagoner DR. New hope for the prevention of recurrent atrial fibrillation Eur Heart J 2004;25:1089-1090.[Free Full Text]
  9. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization Ann Thorac Surg 2005;79:1530-1535.[Abstract/Free Full Text]
  10. Katz M. Multivariable analysis. Cambridge: Cambridge University Press; 1999.
  11. Malouf JF, Kanagala R, Al Atawi FO, et al. High sensitivity C-reactive protein: a novel predictor for recurrence of atrial fibrillation after successful cardioversion J Am Coll Cardiol 2005;46:1284-1287.[Abstract/Free Full Text]
  12. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation Circulation 2003;108:3006-3010.[Abstract/Free Full Text]
  13. 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;111:2881-2888.[Abstract/Free Full Text]
  14. Gaudino M, Andreotti F, Zamparelli R, et al. The –174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillationIs atrial fibrillation an inflammatory complication?. Circulation 2003;108(Suppl 1):II195-II199.[Medline]
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  16. Amar D, Zhang H, Heerdt PM, et al. Statin use is associated with a reduction in atrial fibrillation after noncardiac thoracic surgery independent of C-reactive protein Chest 2005;128:3421-3427.[Medline]
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