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Eur J Cardiothorac Surg 2002;22:939-943
© 2002 Elsevier Science NL

Prediction of atrial fibrillation after coronary artery bypass grafting by measuring atrial peptide levels and preoperative atrial dimensions

T. Hakalaa*, A. Hedmanb, A. Turpeinenb, R. Kettunenb, O. Vuolteenahoc, M. Hippeläinena

a Department of Thoracic and Cardiovascular Surgery, Kuopio University Hospital, Kuopio, Finland
b Department of Cardiology, Kuopio University Hospital, Kuopio, Finland
c Department of Physiology, Oulu University, Oulu, Finland

Received 15 May 2002; received in revised form 30 July 2002; accepted 27 August 2002.

* Corresponding author. Tel.: +358-17-173311; fax: +358-17-173746
e-mail: tapio.hakala{at}kuh.fi


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: We prospectively tested the hypothesis that atrial enlargement and increased level of atrial natriuretic peptide, N-terminal atrial natriuretic peptide and brain natriuretic peptide would predict atrial fibrillation after coronary artery bypass grafting. Methods: Eighty-eight elective coronary artery bypass grafting patients had preoperative echocardiographic assessment. The level of atrial natriuretic peptide, N-terminal atrial natriuretic peptide and brain natriuretic peptide were measured preoperatively. Patients were ECG- monitored during the whole hospital stay. Results: Thirty one (35.2%) patients had postoperative atrial fibrillation. In univariate analysis increased age (P=0.003), enlargement of left and right atria (P=0.002 and P=0.004, respectively) and increased level of preoperative atrial natriuretic peptide and N-terminal atrial natriuretic peptide (P=0.016 and P=0.03, respectively) were associated with postoperative atrial fibrillation. There was correlation between the age and level of N-terminal atrial natriuretic peptide (r=0.45 and P<0.001). In multivariate analysis only age and the left atrial enlargement were independent predictors of postoperative atrial fibrillation (P=0.02 and P=0.01). Conclusion: Left atrial enlargement was independent predictor for postoperative atrial fibrillation. However, atrial peptides were associated with age and did not independently predict postoperative atrial fibrillation. In addition, the wide variation of the peptide levels renders the implementation of this measure in clinical practice superfluous.

Key Words: Coronary artery bypass surgery • Atrial fibrillation • Atrial enlargement • Atrial natriuretic peptide


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
The postoperative incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) varies between 16 and 33%. AF depletes hospital resources and is a major contributing factor of increasing morbidity after CABG [1–4].

There is currently no reliable established method for preoperative identification of those patients at high risk for AF after CABG, and the pathophysiological mechanism of AF after CABG is not clear. However, a number of predisposing factors have been shown to be related to AF after CABG. The most often reported risk factor is increased age [1–4]. In addition, there are controversial studies about the importance of atrial dimensions as a predictor of AF following CABG [5,6]. Only in one study have the levels of atrial natriuretic peptides been compared between patients who sustained AF and those who remained in sinus rhythm [6].

The aim of our study was to evaluate further potential clinical predictors of AF after CABG. Particularly, we tested the hypothesis that increased atrial sizes and increased level of atrial peptides would be predictors for AF after CABG. Secondarily we measured atrial peptides in the early postoperative period.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
Between November 1999 and November 2000, 640 patients had elective CABG using cardiopulmonary bypass in Kuopio University Hospital. From those patients 100 patients were randomly enrolled into the study providing they fulfilled the inclusion criteria: elective primary isolated CABG using cardiopulmonary bypass. The exclusion criteria were: previous AF episodes, acute myocardial infarction within a month before the surgery and ejection fraction less than 50% as measured with echocardiography or left ventricle kine-angiogram. Twelve out of these randomly selected 100 patients were excluded from the study. The reasons for exclusions were: four patients also had unplanned mitral valve procedure, five patients unexpectedly were operated on without cardiopulmonary bypass with beating heart due to calcification of ascending aorta and three patients had incomplete data of atrial peptides. Altogether, 88 patients formed the study population. All procedures used in this study were approved by the Kuopio University Ethical Committee. Informed consent was obtained from every patient before entering the study.

2.1. Operative techniques
The ascending aorta was cannulated for arterial line and a double-stage single venous cannula was inserted through the auricle of the right atrium. Aortic root venting was used routinely. Cardiopulmonary bypass with moderate systemic hypothermia (temperature of venous blood 32 °C) and moderate hemodilution (hematocrit >0.22) was used with flow rates of 2.2-2.4 l/m2 and mean perfusion pressure of 50–85 mmHg. Intermittent cold crystalloid cardioplegia was administered through antegrade route. Peripheral and central anastomoses were constructed during single aortic occlusion. Cardioplegia solution consisted of magnesium 16 mmol/l and no extra magnesium substitution was administered.

2.2. Postoperative protocol
After the operation patients were followed in the intensive care unit (ICU) and were weaned off the ventilator when they fulfilled the following criteria: hemodynamic stability, peripheral temperature more than 32 °C, co-operativity, and no major bleeding. Chest drains were removed on the first postoperative day and the patients were moved to the surgical ward when they had hemodynamic and respiratory stability. Postoperative continuous ECG monitoring was continued during the whole period of hospital stay to detect all episodes of AF and 12-lead ECG was used as necessary to confirm the rhythm abnormality. The ECG recordings were checked daily by the surgeon. Postoperatively potassium level was measured twice a day during the study period and potassium was administered as needed to keep the potassium serum concentration within normal range. Aspirin was administered 100 mg daily starting the first postoperative day. ß-Blocking medication (metoprolol) was continued in every patient starting on the first postoperative day and the dosage was titrated for a resting heart rate of 60–90 beats/min. No other anti-arrhythmic medication was given.

2.3. Echocardiography and atrial peptides
Preoperatively each patient had transthoracic echocardiographic evaluation (HP Sonos 2500, Hewlett Packard, USA). The sizes of left and right atria were measured in the apical four-chamber view.

Venous blood samples from the cubital vein for the analysis of atrial natriuretic peptide (ANP), N-terminal natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP) were taken preoperatively, and 18 and 28 h postoperatively. ANP and BNP were extracted from plasma using SepPak C18 cartridges. N-ANP was assayed directly from unextracted plasma. The radioimmunoassay protocols have been described previously for ANP [7] and N-ANP [8]. The BNP assay was performed with the same protocol as ANP. The sensitivities of the ANP, N-ANP, BNP assays were 1.0, 40 and 0.5 pmol/l plasma, respectively. The within and between assay coefficients of variation in each assay were <10 and <15%, respectively. The different assays were specific for the particular peptide. The ANP and N-ANP assays cross-reacted fully with proANP and the BNP assay with proBNP. With these methods, the following plasma levels (mean±SD) were detected in healthy adults aged 20–55 years: ANP 10.9±4.0 pmol/l, BNP 3.8±3.4 pmol/l and N-ANP 227±84 pmol/l [8].

2.4. Postoperative complications
The rhythm was defined as AF when there was no consistent P waves before each QRS complex and ventricular rate was irregular. AF episodes lasting longer than 5 min were recognized. The occurrence of the first AF was the endpoint of our study. Perioperative myocardial infarction was defined as a new Q wave and increases of creatinine kinase-MB mass over 50 µg/l, which is ten times over the upper limit of normal range. Stroke was defined by symptoms of neurologic deficit and verified by computed tomography.

2.5. Statistical analysis
Values are expressed as mean±SD. Differences in continuous and categorized variables were tested by unpaired t-test and chi-square test, respectively. Paired t-test was used to test the differences of preoperative and postoperative values of atrial peptides. Correlation between variables was tested by Pearson's correlation (continuous variables) or Spearman's rank order correlation (categorized variables). If a variable predicted AF in univariate analysis it was entered into backward stepwise logistic regression analysis in order to assess the independent predictors of AF. Because selection of variables that correlate with each other may result in multicollinearity and overfitting of the model, only one clinically relevant variable was chosen in case of correlation. The limit for statistical significance was P<0.05. All the statistical procedures were performed by the SPSS 9.0 statistical package (SPSS Inc., Chicago, IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Seventy-eight percent of the patients were male and their average age was 61.8±9.9 years. All patients had ß-blocking medication preoperatively. Postoperative AF occurred in 31 of 88 (35.2%) patients. The average time from the operation to the first AF episode was 56±22 h. The patients’ demographics and operative data are summarized in Table 1.


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  		Table 1. Demographic, operative and postoperative data and univariate P-valuea

 
There were no hospital deaths in the study group. Two patients, both in the sinus rhythm (SR) group had to be reoperated, due to postoperative bleeding. There were no perioperative myocardial infarctions or postoperative low output syndromes in the study group. Two perioperative strokes occurred, one in both groups. One superficial sternal wound infection occurred in the AF group.

Atrial dimensions and other results of transthoracic echocardiographic assessment and the values of ANP, N-ANP and BNP levels are presented in Table 2. Results of analysis of atrial areas are illustrated in Fig. 1 .


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  		Table 2. Atrial areas and values of ANP, N-ANP and BNP, and univariate P-valuea

 


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  		Fig. 1. Results of analysis of atrial areas. Black boxplots are patients who remained in sinus rhythm and open boxplots are patients who went into atrial fibrillation. P-values are less than 0.05 between patients group both in the areas of right and left atrias.

 
Increased age, and increased left and right atrial dimensions were associated by univariate analysis with increased risk for postoperative AF. Increased level of ANP and N-ANP both preoperatively and postoperatively were also associated with increased risk for AF. There was no significant association between the level of BNP and the risk for postoperative AF. The levels of all atrial peptides increased significantly after the operation compared with preoperative values. There was a significant correlation between age and the level of N-ANP (r=0.451 and P<0.01). The correlation is illustrated in Fig. 2 . Diabetes was associated by univariate analysis with increased risk for postoperative AF and there was tendency between higher body mass index and postoperative AF as well as between lower preoperative hemoglobin value and postoperative AF.



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  		Fig. 2. Correlation between patients' age and value of preoperative N-ANP.

 
3.1. Multivariate analysis
The correlation between the sizes of left and right atria was significant (r=0.59, P<0.001) and only the size of left atria was taken to multivariate analysis. The left atrium was chosen because of left atrial predominance in the initiation and maintenance of AF [9]. Atrial size was not correlated with the level of ANP or N-ANP. The correlation between ANP and N-ANP was so strong (r=0.64, P<0.001) that only preoperative N-ANP value was taken to multivariate analysis.

Two variables were found to be independent predictors of postoperative AF. Age was one predictor of AF with an odds ratio (OR) of 1.07 for each increasing year above the lower border of the age range (P=0.02, 95% confidence interval 1.01–1.12). The other independent predictor was the cross-sectional area of the left atrium. Each increasing cm2 of left atrial area increased the risk of AF 1.29 fold (P=0.01, 95% confidence interval 1.05–1.57). Diabetes was not independent predictor for postoperative AF by multivariate analysis.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The incidence of postoperative AF was 35.2%, being similar to the other reports wherein AF frequency has been reported to be from 27 to 33% [1,3]. The incidence of AF after CABG has not decreased during last decade. One reason is possibly that patients undergoing CABG today are older than previously. Another reason may be that routine continuous rhythm monitoring employed nowadays reveals episodes of AF that would not have been detected clinically and may have been missed in previous analyses.

Increased age was an independent predictor of postoperative AF. This is in agreement with other studies [1–4,10]. One reason might be that age-related changes in the heart, such as dilation of the heart, increased fibrosis and decreased conduction tissue, makes heart more susceptible to atrial arrhythmias after CABG [11].

Preoperative concentration of ANP and N-ANP were predictors of postoperative AF with univariate analysis, but they did not remain independent predictors of AF with multivariate analysis. Jideus et al. did not find any association between preoperative values of ANP or N-ANP and AF after CABG [6]. In non-operative patients, plasma ANP and N-ANP have been reported to be raised in patients with heart failure and to increase further as the severity of the disease progresses [12,13]. N-ANP is a marker for symptomless left ventricular dysfunction [14]. Therefore, we excluded patients who had an ejection fraction less than 50% from our study, in order to exclude left ventricular dysfunction as a reason for increased level of ANP. In addition it is known that ANP and N-ANP levels are markedly increased in patients with acute myocardial infarction [15,16] and thus we also excluded patients who had had myocardial infarction within 30 days prior to the operation. Yamada et al. have shown in non-operative patients that elevated ANP levels are predictors of paroxysmal AF in patients with congestive heart failure [17]. However, in our study ANP and N-ANP correlated with age and was not an independent predictor of AF when adjusted for age.

The level of N-ANP and ANP increased significantly after the operation compared with preoperative values. Surgical trauma of atria and atrial wall stress due to fluid retention are the most plausible explanations for this change.

We found correlation between the patients’ age and the level of N-ANP, so both patients’ age and the level of N-ANP could not be taken to multivariate analysis. The main stimulus of release of N-ANP prohormone from the atrium is atrial wall stress [18]. The association between elevated ANP levels and postoperative AF might not be a direct result of elevated N-ANP level but is indirectly caused by left atrial wall stress. Age-related changes like fibrosis in the atria increase atrial wall stress and stimulate the release of ANP prohormone. This may explain the correlation between increased age and increased level of N-ANP.

We found left atrial enlargement to be an independent predictor of postoperative AF. As a result of left atrial dilatation, the distribution of atrial refractoriness is not uniform. Sato et al. have shown that abnormal dispersion of refractoriness makes the atrium more vulnerable to the development of AF after a cardiac operation [19]. Our results are in agreement with Ducceschi et al. who found the same result in their study [5]. However, Jideus et al. did not find atrial enlargement to be predictor of AF after CABG [6]. Zaman et al. did not find an association between atrial enlargement and AF after CABG, but their study comprised only 64 patients and was a subgroup of a larger study population [10].

Preoperative atrial enlargement and concomitantly elevated preoperative plasma levels of atrial natriuretic peptides indicate an existence of pathophysiologic substrate for postoperative atrial fibrillation. The elevated levels of atrial natriuretic peptides suggest that any pathophysiologic mechanism leading to an increase in atrial wall stress submits wall tissue to electrical chaos and fibrillation. The increased postoperative levels of the peptides indicate the same mechanism to be significant at the initiation of the atrial fibrillation. In the present series, those patients with left ventricular systolic dysfunction were excluded. However, not only systolic but also diastolic ventricular dysfunction may cause an increase in filling pressure leading to an increase in atrial wall stress. The wide overlapping of the plasma values of atrial natriuretic peptides between those patients with or without postoperative atrial fibrillation does not exclude, however, other pathophysiologic mechanisms, e.g. increased collagen content of the atrial tissue especially for older ages. Regardless of that, the observed positive correlation between the plasma levels of natriuretic peptides and age indicate that both of the mechanisms may remain significant in the more elderly patients.

Due to the wide overlapping of the plasma concentrations of the atrial peptides between the two patient groups, the preoperative peptide measurements may offer only limited value for the assessment of the risk of postoperative atrial fibrillation.


   Acknowledgments
 
We thank Dr. Graham V. Lees for the linguistic revision of the text.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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