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Ann Thorac Surg 2007;84:61-66
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

ß-Blocker Prophylaxis for Atrial Fibrillation After Coronary Artery Bypass Grafting in Patients With Sympathovagal Imbalance

Marco Budeus, MDa,*, Peter Feindt, MDb, Emmeran Gams, MDb, Heinrich Wieneke, MDa, Stefan Sack, MDa, Raimund Erbel, MDa, Christian Perings, MDc

a Department of Cardiology, West-German Heart Centre, University of Duisburg-Essen, Essen, Germany
b Department of Thorax- and Cardiovascular Surgery, Surgical Clinic and Policlinic B, Heinrich-Heine-University, Duesseldorf, Germany
c Department of Cardiology and Angiology, University Hospital Herne, Ruhr-University Bochum, Herne, Germany

Accepted for publication February 6, 2007.

* Address correspondence to Dr Budeus, Department of Cardiology, West-German Heart Centre, University of Duisburg-Essen, Hufelandstr. 55, D-45122 Essen, Germany (Email: marco.budeus{at}medizin.uni-essen.de).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Atrial fibrillation (AF) is the most common arrhythmia after coronary bypass grafting (CABG) resulting in a prolonged hospital stay and higher costs. The withdrawal of ß-blocker and a sympathovagal imbalance were identified as risk factors for AF.

Methods: In our study we performed a measuring of standard deviation of all normal RR intervals (SDNN) among 142 consecutive patients with ß-blocker therapy before CABG in order to identify a collective who had an increased risk due to a withdrawal of ß-blocker medication. A sympathovagal imbalance was predefined as a SDNN below 30 ms. Patients were divided into four groups according to the results of SDNN and the continuous ß-blocker therapy: group I: SDNN ≤ 30 ms or less and withdrawal of ß-blocker therapy (26 patients); group II: SDNN ≤ 30 ms and continuously ß-blocker therapy (33 patients); group III: SDNN > 30 ms and withdrawal of ß-blocker therapy (40 patients); group IV: SDNN > 30 ms and continuous ß-blocker therapy (43 patients).

Results: Atrial fibrillation occurred in 39 patients (27%) after surgery. Patients of group I showed a higher incidence of AF (14 of 26 patients, 54%) than patients of group II (7 of 33 patients, 21%; p < 0.009), patients of group III (8 of 40 patients, 20%; p < 0.004), or patients of group IV (10 of 43 patients, 23%; p < 0.01). We found a significantly higher incidence of diabetes mellitus (47 vs 14% of patients; p < 0.0001) in patients with a sympathovagal imbalance than patients with a SDNN above 30 ms.

Conclusions: The results of our study suggest a sympathovagal imbalance and withdrawal of a ß-blocker therapy increase the risk of postoperative AF. A continuous ß-blocker therapy reduces the risk especially in patients with a sympathovagal imbalance and should always be practiced.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Atrial fibrillation (AF) is a frequent complication after coronary bypass grafting (CABG) with a reported incidence between 10% and 40% [1–5]. The appearance of the arrhythmia after coronary artery surgery could result in an increased morbidity, a prolonged hospitalization and higher costs [3–5]. Different risk factors, such as advanced age, a stenosis of the right coronary artery, a lower left ventricular ejection fraction, a longer filtered P wave duration measured by a P wave triggered P wave signal averaged electrocardiogram (ECG), or an autonomic dysfunction characterized as low vagal tone and increased sympathetic tone [5–9], could be identified. In addition, a withdrawal of ß-blocker therapy after CABG is also a risk factor of AF [1–9]. We could show, on the basis of a small group of patients, that patients with a sympathovagal imbalance characterized by a lower chemoreflexsensitivity (≤3.0 ms/mm Hg) or a lower standard deviation of all normal RR (R of QRS complex) intervals (SDNN) (≤30 ms) were more likely to get AF through a withdrawal of ß-blocker therapy after CABG [5]. The margin of SDNN was determined in a previous publication [10]. It was the aim of the retrospective study to investigate our observation on the basis of a large group of patients with ß-blocker therapy in order to classify another group of patients having a high risk of postoperative AF.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
We included 142 consecutive patients with sinus rhythm and a ß-blocker therapy undergoing CABG without a history of paroxysmal, persistent, or permanent AF before surgery. All patients had a 24-hour Holter ECG (Marquette Holter recorder 8500 with five leads, Marquette Electronic, Inc, Milwaukee, WI) one day before surgery for recording of a normal sinus rhythm. The Institutional Review Board approved the study and patients gave written, informed consent of the study.

Patients underwent a cardiac catheterization for coronary heart disease performed within one to six weeks before their scheduled surgery. The ejection fraction (EF) was calculated by angiography. A stenosis was defined as narrowing of greater than or equal to 70% of lumen diameter in the right, left anterior or circumflex artery and greater than or equal to 50% in the left main artery. A stenosis of the left main artery was equated to a stenosis of the left anterior and circumflex artery.

The patients were divided into four groups according to the results of SDNN and the continuation of the ß-blocker therapy after surgery (Fig 1). A sympathovagal imbalance was predefined as a SDNN of 30 ms or less [5]. The patients with a sympathovagal imbalance were divided into patients with (group I) and without (group II) a withdrawal of ß-blocker therapy after CABG. Patients with a SDNN greater than 30 ms were also divided into a group with (group III) and without (group IV) a withdrawal of ß-blocker therapy after CABG (Fig 1). The medication was directed by the cardiac surgery team that was blinded to the result of SDNN measurement.


Figure 1
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  		Fig 1. Flow diagram of the study. (CABG = coronary artery bypass grafting; SDNN = standard deviation of all normal RR intervals.)

 
We excluded patients with valvular prosthesis, undergoing valvular surgery, and those affected by permanent or paroxysmal AF. A short-term SDNN for a period of 15 minutes was performed in all patients one to seven days before the surgery. Left atrial size was evaluated by echocardiography at the same time.

All patients were monitored by a continued Holter ECG (Marquette Holter recorder 8500 with 5 leads, Marquette Electronic Inc) for seven days after surgery. Atrial fibrillation was defined as present when it was documented to have occurred and lasted for at least 10 minutes [5, 7].

Measurement of Standard Deviation of all Normal RR Intervals
The analysis of SDNN was described in detail in a former publication [5]. In our study, the SDNN (Predictor, Kaiser Medizintechnik, Bad Hersfeld, Germany) was analyzed over 15 minutes by the variations of consecutive heart beats or RR intervals in the morning in all patients. Temporal analysis of SDNN included measurements of the heart frequency and standard deviation of RR intervals, which detects abnormalities of autonomic function [11, 12]. All ectopic beats were removed and an interpolation was performed for the analysis of SDNN. The margin of SDNN was predefined as a SDNN of 30 ms or less [5].

Echocardiography
An M-mode and two-dimensional echocardiography (model SSH-160 A, Toshiba Corp, Tochigi-Ken, Japan) was performed in all patients in the left lateral supine position in order to determine left atrial size.

Surgical Procedure
After the initiation of cardiopulmonary bypass, myocardial protection was achieved by cooling to 28°C and cold crystalloid cardioplegia or with cross-clamp fibrillation and a temperature of 32°C. Conduits for bypass included, whenever possible, the internal mammary artery, the saphenous veins, or a combination of both.

Statistics
All continuous variables are presented as mean values ± standard deviation. The statistical package used was SPSS 12.0 for Windows (SPSS Inc, Chicago, IL). Differences between the values were evaluated for statistical significance using the Mann-Whitney U test and {chi}2 test for baseline characteristics. For continuous variables with normal distribution, the Kruskal-Wallis analysis of variance with post hoc Student t test were used. A measuring of the linear association between two variables was evaluated by using the Pearson correlation coefficient. All statistical tests were 2-tailed. We included diabetes mellitus, a SDNN of 30 ms or less, and the withdrawal of ß-blocker therapy after CABG in the univariate analysis. A multivariate Cox regression analysis was performed with diabetes mellitus, and the combination of SDNN 30 ms or less and the withdrawal of ß-blocker therapy after CABG. For all variables with at least a moderate level of association (p < 0.1), we estimated the individual odds ratios with confidence intervals. The Kaplan-Meier analysis with the log-rank test was used to compare the probability of AF with preoperative and postoperative values. A p value of 0.05 or less was considered as significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
No patient had a calcium antagonist therapy. A sympathovagal imbalance was presented among 59 patients (42%). The four groups were comparable in baseline characteristics (Table 1), operative and postoperative values (Table 2) with the exception of a higher incidence of diabetes mellitus (47% vs 14% of patients, p < 0.0001) in patients with a sympathovagal imbalance.


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  		Table 1 Clinical Details of Patients
 

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  		Table 2 Operative and Postoperative Values of Patients With and Without Atrial Fibrillation
 
Postoperative Follow-Up
Postoperative AF occurred in 39 (27%) of 142 patients with a peak incidence between the second and fourth day. The postoperative ß-blocker withdrawal was significantly higher in patients with postoperative AF than in patients with sinus rhythm (22 of 66 [33%] patients vs 17 of 76 [22%] patients, p < 0.012). The ß-blocker therapy was withdrawn because of hypotension (54 patients), sinus bradycardia (7 patients), or sinus bradycardia in combination with hypotension (5 patients). The ß-blocker was withdrawn in most cases at the first day (98%) and in one case at the second day (2%) after surgery. The onset of AF was significantly higher in group I (14 of 26 patients, 54%) than when compared with group II (7 of 33 patients, 21%; p < 0.009), group III (8 of 40 patients, 20%; p < 0.004), or group IV (10 of 43 patients, 23%; p < 0.01).

The operative values were similar among the groups (Table 2). Pneumonia, a prolonged (>24 hours) respiratory treatment or the development of a thoracotomy syndrome postoperatively were not different among the four groups. A significant difference in values of creatine kinase, creatine kinase (cardiospecific), glutamate oxalacetate transaminase, lactate dehydrogenase, and C-reactive protein measured one day after surgery could also not be detected among all groups.

Predictors of Atrial Fibrillation
The predictive power of a SDNN 30 ms or less in combination with a ß-blocker withdrawal achieved the best predictive value for AF (Table 3). This combination achieved a specificity of 78%, a sensitivity of 54%, a positive predictive value of 36%, a negative predictive value of 88%, and an accuracy of 73% for prediction of AF. A SDNN 30 ms or less achieved no statistical significance in patients with postoperative AF (21 of 59 [36%] patients vs 15 of 83 [18%] patients, p < 0.068). Neither a SDNN 30 ms or less nor a ß-blocker withdrawal was a significant independent risk factor for postoperative AF (Table. 4).


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  		Table 3 Specificity, Sensitivity, and Predictive Value of SDNN ≤ 30 ms and Withdrawal of ß-Blocker
 

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  		Table 4 Univariate and Multivariate Predictors of Atrial Fibrillation After Coronary Artery Bypass Grafting
 
A combination of SDNN 30 ms or less with ß-blocker withdrawal achieved a statistical significance in the same regression model (Table 5). Diabetes mellitus also was an independent predictor of AF in both regressions models (Tables 4, 5). A continuous ß-blocker therapy resulted in significant reduction of AF (odds ratio, 0.37; 95% CI, 0.17 to 0.82, p < 0.014). Figure 2 shows, on the basis of a Kaplan-Meier analysis, the significantly higher incidence of AF among group I patients than the other groups.


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  		Table 5 Univariate and Multivariate Predictors of Atrial Fibrillation After Coronary Artery Bypass Grafting in Combination
 

Figure 2
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  		Fig 2. Kaplan-Meier analysis of percentages of patients remaining free of atrial fibrillation (AF) after coronary artery bypass grafting. (Group I: SDNN < 30 ms and withdrawal of ß-blocker therapy. Group II: SDNN < 30 ms and continuous ß-blocker therapy. Group III: SDNN > 30 ms and withdrawal of ß-blocker therapy. Group IV: SDNN > 30 ms and continuous ß-blocker therapy.) (Odds ratio 3.5, p < 0.011; {blacksquare} = group I; {diamondsuit} = group II; {blacktriangleup} = group III; bullet = group IV; SDNN = standard deviation of all normal RR intervals.)

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
In the present study a sympathovagal imbalance, characterized by a SDNN 30 ms or less with withdrawal of the ß-blocker therapy, increases the risk for AF after CABG. Sympathovagal imbalances in combination with a ß-blocker withdrawal and diabetes mellitus have been determined as powerful predictors of postoperative development of AF.

Autonomic Nervous System
We showed, in our present and former studies, that patients with a sympathovagal imbalance had a higher risk for AF due to the ß-blocker withdrawal [5]. The analysis of SDNN provides information on variant distribution as a function of frequency and is a reliable marker of the autonomic tone and its variations [11, 12]. Alterations of the autonomic tone could be observed after CABG, but only the analysis of the SDNN did not identify patients at risk of AF [5, 13]. The lower SDNN after CABG was mainly attributed to a reduced parasympathetic activity [9, 14]. An increased level of norepinephrine was noticed immediately after surgery followed by a plateau and a decline after 40 hours with a higher level among patients with AF [7]. The autonomic nervous system modulated dispersion of atrial refractory, which could evoke AF due to a shortening of the atrial refractory period [15, 16].

Withdrawal of ß-Blocker Therapy
The withdrawal of ß-blocker medication was associated with an increased risk of AF after surgery [1–9]. The risk of AF after CABG was nearly doubled as a result of a ß-blocker withdrawal in combination with a sympathovagal imbalance [5, 7–9] in comparison with a sole ß-blocker withdrawal [1–9] in our study. Patients with a ß-blocker therapy showed a hyperadrenergic status secondary to ß-receptor up-regulation that was increased after the withdrawal of ß-blockers [17, 18]. The postoperative increased sympathetic activity [7] tended to favor an atrial automatism, which was noted by short atrial tachycardias [5, 17, 18]. This could explain the effect of ß-blockers for preventing postoperative AF and the lower incidence of AF during a continuous ß-blocker therapy [5, 19, 20].

Diabetes Mellitus
Patients with a sympathovagal imbalance showed a higher incidence of diabetes mellitus, which might be a sign of an autonomic neuropathy [21, 22]. Diabetes mellitus is an additional risk factor of AF [2], which could be explained by a disturbed autonomic nervous system. An increased adrenergic level in combination with a withdrawal of ß-blocker and a disturbed autonomic nervous system could result in an increased risk of AF after CABG [5, 7, 20].

Limitations
We monitored the patients up to the seventh postoperative day. Thus, we could not document an episode of AF after this time, which might have influenced the results of our predictive values; atrial fibrillation was rarely observed after the seventh postoperative day in other studies [1–4, 6–8]. The measurement of SDNN is an indirect method for determining a sympathovagal imbalance. In the present study, neither a SDNN 30 ms or less, nor a ß-blocker withdrawal, was an independent predictor for AF. A statistical significance was achieved with a combination of a SDNN 30 ms or less and a ß-blocker withdrawal. This connection should be examined with a larger patient population in a prospective study.

The results of our study suggest that a sympathovagal imbalance and withdrawal of a ß-blocker therapy increase the risk of postoperative AF. A continuous ß-blocker therapy reduces the risk, especially among patients with a sympathovagal imbalance. A preoperative identification of patients with a sympathovagal imbalance should result in a continuous ß-blocker therapy.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Creswel LL, Schuessler RB, Rosenbloom M, Cox JL. Hazards of postoperative atrial arrhythmias Ann Thorac Surg 1993;56:539-549.[Abstract]
  2. 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]
  3. Mathew JP, Parks R, Savino JS, et al. MultiCenter Study of Perioperative Ischemia Research Group Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization JAMA 1996;276:300-306.[Abstract/Free Full Text]
  4. Frost L, Molgaard H, Christiansen E, Hjortholm K, Paulsen P, Thompson P. Atrial fibrillation and flutter after coronary artery bypass surgery: epidemiology, risk factors and preventive trials Int J Cardiol 1992;36:253-261.[Medline]
  5. Budeus M, Hennersdorf M, Röhlen S, et al. Predicting of atrial fibrillation after coronary bypass grafting: the role of chemoreflexsensitivity and P wave signal averaged ECG Int J Cardiol 2006;106:67-74.[Medline]
  6. Aytemir K, Aksoyek S, Ozer N, Sait A, Oto A. Atrial fibrillation after coronary artery bypass surgery: P wave signal averaged ECG, clinical and angiographic variables in risk assessment Int J Cardiol 1999;69:49-56.[Medline]
  7. Kalman JM, Munawar M, Howes LG, et al. Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation Ann Thorac Surg 1995;60:1709-1715.[Abstract/Free Full Text]
  8. Dimmer C, Tavernier R, Gjorgov N, van Nooten G, Clement DL, Jordaens L. Variations of autonomic tone preceding onset of atrial fibrillation after coronary artery bypass grafting Am J Cardiol 1998;82:22-25.[Medline]
  9. Frost L, Molgaard H, Christiansen EH, Jacobsen CJ, Allermand H, Thomsen PEB. Low vagal tone and supraventricular ectopic activity predict atrial fibrillation and flutter after coronary artery bypass grafting Eur Heart J 1995;16:825-831.[Abstract/Free Full Text]
  10. Budeus M, Hennersdorf M, Wieneke H, Sack S, Erbel R, Perings C. P wave signal averaged ECG and chemoreflexsensitivity in paroxysmal atrial fibrillation Int J Cardiol 2005;100:317-324.[Medline]
  11. Stein PK, Bosner MS, Kleiger RE, Conger BM. Heart rate variability: a measure of cardiac autonomic tone Am Heart J 1994;127:1376-1381.[Medline]
  12. Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology Heart rate variability: standards of measurement, physiological interpretation and clinical use Eur Heart J 1996;17:354-381Circulation 1996;93:1043–65.[Free Full Text]
  13. Hakala T, Vanninen E, Hedman A, Hippelainen M. Analysis of heart rate variability does not identify the patients at risk of atrial fibrillation after coronary artery bypass grafting Scand Cardiovasc J 2002;36:167-171.[Medline]
  14. Niemela MJ, Ariaksinen KEJ, Tahvanainen KUO, Linnaluoto MK, Takkunen JT. Effect of coronary artery bypass grafting on cardiac parasympathetic nervous function Eur Heart J 1992;13:932-935.[Abstract/Free Full Text]
  15. Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Intraatrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog Circulation 1984;70:123-135.[Abstract/Free Full Text]
  16. Kralios FA, Millar CK. Sympathetic neural effects on regional atrial recovery properties and cardiac rhythm Am J Physiol 1981;240:H590-H596.[Medline]
  17. Pires LA, Wagshal AB, Lancey R, Huang SKS. Arrhythmias and conduction disturbances after coronary artery bypass graft surgery: epidemiology, management and prognosis Am Heart J 1995;129:799-808.[Medline]
  18. Bayés de Luna A, Bayés Genis A, Guindo J, Vinolas X, Boveda S, Torner P. Mechanisms favouring and triggering atrial fibrillation Arch Mal Coeur 1994;87:19-25.
  19. Boudalas H, Synder GL, Lewis RP, Kates RE, Karayannocos PE, Vasko JS. Safety and rationale for continuation of propranolol therapy during coronary bypass operation Ann Thorac Surg 1978;26:222-229.[Abstract]
  20. Balcetyte-Harris N, Tamis JE, Homel P, Menchavez E, Steinberg JS. Randomized study of early intravenous esmolol versus oral beta-blockers in preventing post-CABG atrial fibrillation in high risk patients identified by signal-averaged ECG: results of a pilot study Ann Noninvasive Electrocardiol 2002;7:86-91.[Medline]
  21. Osterhues HH, Grossmann G, Kochs M, Hombach V. Heart-rate variability for discrimination of different types of neuropathy in patients with insulin-dependent diabetes mellitus J Endocrinol Invest 1998;21:24-30.[Medline]
  22. Rutter MK, McComb JM, Brady S, Marshall SM. Autonomic neuropathy in asymptomatic subjects with non-insulin-dependent diabetes mellitus and microalbuminuria Clin Auton Res 1998;8:251-257.[Medline]

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