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Increased N-terminal pro-brain natriuretic peptide level predicts atrial fibrillation after surgery for esophageal carcinoma.

AIM
To evaluate the value of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level for predicting postoperative atrial fibrillation (AF) in patients undergoing surgery for esophageal carcinoma.


METHODS
NT-proBNP levels were measured in 142 patients 24 h before and 1 h after surgery for esophageal carcinoma. All patients having a preoperative cardiac diagnosis by electrocardiogram (ECG), remained under continuous monitoring for at least 48 h after surgery, and then underwent clinical cardiac evaluation until discharge.


RESULTS
Postoperative AF occurred in 11 patients (7.7%). AF patients were significantly older (69.6 +/- 12.2 years vs 63.4 +/- 13.3 years, P = 0.031) than non-AF patients. There were no significant differences in history of diabetes mellitus, sex distribution, surgical approach, anastomosis site, intraoperative hypotension and postoperative fever. The preoperative plasma NT-proBNP level was significantly higher in patients who developed postoperative AF (121.3 +/- 18.3 pg/mL vs 396.1 +/- 42.6 pg/mL, P = 0.016). After adjustment for age, gender, chronic obstructive pulmonary disease (COPD), history of cardiac diseases, hypertension, postoperative hypoxia and thoracic-gastric dilation, NT-proBNP levels were found to be associated with the highest risk factor for postoperative AF (odds ratio = 4.711, 95% CI = 1.212 to 7.644, P = 0.008).


CONCLUSION
An elevated perioperative plasma BNP level is a strong and independent predictor of postoperative AF in patients undergoing surgery for esophageal carcinoma. This finding has important implications for identifying patients at higher risk of postoperative AF who should be considered for preventive antiarrhythmic therapy.


INTRODUCTION
Postoperative infections and cardiac events are the major complications after surgery for esophageal carcinoma and the dominating causes of death. Atrial fibrillation (AF) is a frequent arrhythmia after esophageal procedures and is associated with an increased morbidity and mortality and a longer, more expensive hospital stay [1][2][3][4][5] .
In a previous study, we retrospectively studied 63 patients with AF after surgery for esophageal carcinoma in comparison with 126 patients without AF after esophagectomy during the same time. We identified some risk factors as predictors of AF after surgery for esophageal carcinoma, such as postoperative hypoxia, history of obstructive pulmonary disease (COPD), thoracic-gastric dilatation, age older than 65 years, male gender, and history of cardiac disease [6] . However, our ability to accurately identify patients at high risk for AF is still limited. No accurate assessment tool or biomarker has www.wjgnet.com been identified that could predict the occurrence of AF early after esophageal procedures so far. Since a targeted preventive treatment cannot be performed easily, a sensitive blood biomarker that can predict the occurrence of AF in patients after surgery for esophageal carcinoma with a high specificity is desirable.
Brain natriuretic peptide (BNP) is a neurohormone which is stored mainly in myocytes of the cardiac ventricles and released as a result of volume and pressure overload or myocardial damage [7][8][9][10] . N-terminal pro BNP (NT-proBNP) has a longer half life than brain natriuretic peptide and is less influenced by acute therapeutic regimens and clinical deteriorations, making it available for predicting cardiac functions [11][12][13][14] . NT-proBNP has been proved useful for diagnostic and prognostic purposes in patients with congestive heart failure and other cardiac conditions [15][16][17][18] . It was recently reported that increased NT-proBNP can indicate the underlying subclinical predisposition to AF both in patients undergoing cardiac surgery [19] and in patients without a history of cardiac disease [20] . To our knowledge, the ability of NT-proBNP to predict AF after esophageal procedures has not been evaluated. We speculate that an elevated level of NT-proBNP could predict the occurrence of AF early after esophageal procedures. The aim of this study is to determine whether NT-proBNP levels are associated with AF after surgery for esophageal carcinoma.

Patients
One hundred and fifty consecutive patients undergoing elective surgery for esophageal cancer were identified in our hospital from December 2006 to May 2007. Patients with a history of heart failure (n = 3), chronic AF (n = 2), severe renal dysfunction (n = 1), and antiarrhythmic drug use (n = 2) were excluded from the study. One hundred and forty-two patients (113 males and 29 females with an average age of 66.5 years, range 49-86 years) accordant with the inclusion criteria were enrolled in the study.
All patients having a preoperative cardiac diagnosis by electrocardiogram (ECG) remained under continuous monitoring for at least 48 h after surgery and then underwent clinical cardiac evaluation until discharge. AF was defined as absent P wave before the QRS complex with irregular ventricular rhythm on the rhythm strips.
Plasma NT-proBNP concentration was measured 24 h before and soon (within 1 h) after surgery. Blood samples were collected into tubes containing potassium EDTA, centrifuged for 5 min at 1500 r/min and kept at 4℃ . The separated plasma was kept at -30℃ until analysis. NT-proBNP analyses were done with Elecsys Roche Diagnostics commercial kits on a semiautomatic analyzer (Elecsys-2010, Roche Diagnostics, Germany).The test is self-processing and produces a result within 15 min. The precision, analytic sensitivity and stability characteristics of this system have been described elsewhere [21] .

Statistical analysis
Continuous variables are expressed as mean ± SD or median (range) and were compared by Student's t -test.
Chi square test or Fisher's exact test was used to compare groups of categorical data. The relationship between the occurrence of postoperative AF and baseline predictors was assessed with multivariable logistic regression model adjusted for factors presumably associated with AF risk, including advanced age, male gender, COPD, cardiac diseases, hypertension and diabetes mellitus, site of anastomosis, postoperative hypoxia, thoracic-gastric dilation and plasma NT-proBNP [1,[22][23][24][25] . P < 0.05 was considered statistically significant. Statistical analysis was performed using the SPSS 11.0 statistical software package (SPSS, Inc).

RESULTS
The baseline characteristics of the 142 patients are listed in Table 1. The patients were divided into 2 groups according to whether they developed postoperative AF. Postoperative AF occurred in 11 patients (7.7%). Postoperative AF patients were significantly older (69.6 ± 12.2 years vs 63.4 ± 13.3 years, P = 0.031) than non-postoperative AF patients. Patients in the postoperative AF group had a history of COPD (45.5% vs 12.2%, P = 0.021) and cardiac disease more frequently (6.9% vs 27.3%, P = 0.046). Postoperative AF patients had a significantly higher incidence of postoperative hypoxia (36.4% vs 8.4%, P = 0.018) and thoracic-gastric dilation (45.5% vs 12.2%, P = 0.021) than non-postoperative AF patients. There were no significant differences in gender, history of hypertension, diabetes mellitus, surgical approach, anastomosis site, intraoperative hypotension and postoperative fever between the two groups. Preoperative plasma NT-proBNP level was significantly higher in patients who developed postoperative AF (121.3 ± 18.3 pg/mL vs 396.1 ± 42.6 pg/mL, P = 0.016).
In a multivariable logistic regression model adjusted for age, gender, COPD, history of cardiac disease, hypertension, diabetes mellitus, site of anastomosis, postoperative hypoxia, thoracic-gastric dilatation and plasma NT-proBNP, NT-proBNP levels were associated with the highest risk factor for postoperative AF (odds ratio = 4.711, 95% CI = 1.212 to 7.644, P = 0.008) ( Table 2).

DISCUSSION
AF after esophagectomy remains one of the most frequently encountered complications. The incidence of AF in this study was 7.7%, lower than the reported data ranging from 11.3% to 22% [26,27] . Although the causes for postoperative AF after esophagectomy have not been completely disclosed, we speculate that AF after esophagectomy is precipitated by the resolution of inflammatory response following blunt or sharp surgical trauma to sympathovagal nerve fibers supplying the heart, which alters the autonomic modulation of atrial myocardial cells to endogenous catecholamines. Although postoperative AF is self-limited in most cases, it can increase the risk of postoperative stroke [28] . The treatment of postoperative AF requires a prolonged hospital stay and additional costs. Although previous studies [6,22,27] have shown different risk factors for postoperative AF, a definite relation between these factors and occurrence of AF has not been well established. A proper preventive treatment of AF is still a challenge. Even if preventive therapies with antiarrhythmic agents can reduce the occurrence of postoperative AF, their use has been limited because of potential side effects [29] .
BNP and NT-proBNP are members of the natriuretic peptide family synthesized and secreted by the ventricular myocardium. The natriuretic peptide family plays a role in regulation of the cardiovascular system [30] . Moreover, it was reported that an elevated NT-proBNP level can be used as a diagnostic and prognostic marker in patients with congestive heart failure, myocardial infarction, unstable angina and left ventricular hypertrophy [15][16][17][18] .
The present study evaluated the role of NT-proBNP in predicting postoperative AF in patients undergoing surgery for esophageal carcinoma. The results showed that an elevated level of plasma NT-proBNP obtained before or soon after surgery for esophageal carcinoma was a strong and independent predictor of the occurrence of postoperative AF, suggesting that patients can be stratified according to their risk of postoperative AF. A targeted preventive therapy may be performed only for high risk patients with an elevated NT-proBNP level before or soon after esophageal surgery to prevent the occurrence of operative AF. Low-risk patients with a high negative predictive value of NT-proBNP should not receive any preventive treatment.
Our study provided a new prospective in terms of preventive strategies against postoperative AF. It was reported that NT-proBNP-tailored therapy reduces the occurrence of cardiovascular events in patients with heart failure [11,12] . Further studies are needed to demonstrate that reduction in this marker before esophageal surgery is paralleled to a consequent reduction in the risk of AF occurrence. Our study has some limitations, such as a small number of patients, NT-proBNP determined only once after esophagectomy.
In conclusion, an elevated level of perioperative NT-proBNP is a strong and independent predictor of AF occurrence in patients undergoing surgery for esophageal carcinoma.

Background
Atrial fibrillation (AF) is a frequent arrhythmia after esophageal procedures and is associated with an increased morbidity and mortality. Although some risk factors for AF can be predicted after surgery for esophageal carcinoma, no accurate assessment tool or biomarker has been identified that can predict the occurrence of AF early after esophageal procedures. Therefore, a sensitive blood biomarker that can predict the occurrence of AF in patients after surgery for esophageal carcinoma with a high specificity is desirable.

Research frontiers
Previous studies have identified some risk factors as predictors of AF after surgery for esophageal carcinoma, such as postoperative hypoxia, history of obstructive pulmonary disease (COPD), thoracic-gastric dilatation, age over 65 years, male gender, and history of cardiac disease. However, the ability to accurately identify patients at a high risk for AF is still limited.

Innovations and breakthroughs
This study evaluated the role of NT-proBNP in predicting postoperative AF in patients undergoing surgery for esophageal carcinoma. The results showed that an elevated level of plasma NT-proBNP obtained before or soon after surgery for esophageal carcinoma was a strong and independent predictor of the occurrence of postoperative AF. These results may allow us to stratify patients according to their risk of postoperative AF and have important clinical implications.

Applications
An elevated level of perioperative NT-proBNP is a strong and independent predictor of AF occurrence in patients undergoing surgery for esophageal carcinoma. This finding may allows us to stratify patients with perioperative risk for AF and to plan preventive strategies for selected high-risk patients.

Terminology
N-terminal pro-brain natriuretic peptide (NT-proBNP) is a neurohormone which is stored mainly in myocytes of the cardiac ventricles and released as a result of volume and pressure overload or myocardial damage. NT-proBNP has been proved useful for diagnostic and prognostic purposes in patients with congestive heart failure and other cardiac conditions.

Peer review
In this study, the authors examined whether NT-proBNP level is associated with AF after surgery for esophageal carcinoma, showing that an elevated perioperative plasma NT-proBNP level is an independent predictor of postoperative AF in patients undergoing surgery for esophageal carcinoma. This study has certainly provided important implications for identifying higher risk patients.