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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 2  |  Page : 58-63

Relationship between apelin and new-onset atrial fibrillation after coronary artery bypass grafting: a prospective cohort study and retrospective case-control clinical trial


General Hospital of Shenyang Military Region, Shenyang, Liaoning Province, China

Date of Web Publication7-Jul-2016

Correspondence Address:
Shu Xu
General Hospital of Shenyang Military Region, Shenyang, Liaoning Province
China
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Source of Support: This study was supported by the Science and Technology Project of Liaoning Province of China, No. 2012225005., Conflict of Interest: None


DOI: 10.4103/2468-5658.184745

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  Abstract 

Background: Coronary atherosclerotic heart disease as a chronic degenerative disease is the most common type of organ damage caused by atherosclerosis. Coronary artery bypass grafting is an internationally accepted treatment for coronary atherosclerotic heart disease. However, new-onset atrial fibrillation is a common complication after grafting, and its initiation and maintenance might be associated with levels of the peptide apelin.
Methods/Design: A prospective cohort study and retrospective case-control clinical trial will be performed at the Department of Cardiac Surgery, General Hospital of Shenyang Military Region, China. We will recruit 120 patients without a history of atrial fibrillation and scheduled to undergo coronary artery bypass grafting. (1) Cohort study: patients will be assigned to two groups according to preoperative plasma apelin levels: high apelin (> 250 pg/mL) and low apelin (≤ 250 pg/mL). Seven days after surgery, the incidence of new-onset atrial fibrillation will be compared between the two groups. (2) Case-control study: those patients with new-onset atrial fibrillation will comprise the atrial fibrillation group, and those without will form the control group. MRI findings, and levels of plasma apelin, brain natriuretic peptide, and hypersensitive C-reactive protein, will be compared between the two groups 7 days postoperatively.
Discussion: This trial is designed to investigate whether apelin can be used as an indicator to predict postoperative atrial fibrillation in patients with coronary atherosclerotic heart disease, and to provide an objective basis for the clinical selection of a preventive intervention program for atrial fibrillation.
Trial registration: This trial was registered at ClinicalTrial.gov (NCT02807532).
Ethics: The study protocol has acquired written approval from the Chinese Ethics Committee of Registering Clinical Trials (approval No. ChiECRCT-20150011), and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association.
Informed consent: Written informed consent will be obtained from each subject.

Keywords: clinical trial; coronary atherosclerotic heart disease; atrial fibrillation; apelin; atherosclerosis; cohort study; case-control study


How to cite this article:
Xu S, Li Z, Jiang H, Wu Hb, Tao Ds, Han Js, Hou P, Wang Hs. Relationship between apelin and new-onset atrial fibrillation after coronary artery bypass grafting: a prospective cohort study and retrospective case-control clinical trial. Clin Trials Degener Dis 2016;1:58-63

How to cite this URL:
Xu S, Li Z, Jiang H, Wu Hb, Tao Ds, Han Js, Hou P, Wang Hs. Relationship between apelin and new-onset atrial fibrillation after coronary artery bypass grafting: a prospective cohort study and retrospective case-control clinical trial. Clin Trials Degener Dis [serial online] 2016 [cited 2018 Dec 14];1:58-63. Available from: http://www.clinicaltdd.com/text.asp?2016/1/2/58/184745

Conflicts of interest
None declared.
Author contributions
HSW designed this study protocol. SX conceived and revised the manuscript. HJ, HBW and DST recruited patients, performed surgery and collected specimens. JSH participated in statistical analysis. ZL and PH collected specimens and ensured the integrity of the data. All authors read and approved the final version of this manuscript.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.



  Background Top


Atherosclerosis is a systematic and progressive pathological process, which commonly occurs in the intima of large and medium-sized arteries. The disease can lead to degenerative, proliferative, non-inflammatory lesions; thickening, hardening, and loss of elasticity of the vascular wall, and vascular stenosis; and reduced arterial blood flow. Eventually, organ damage occurs. Coronary atherosclerotic heart disease is the most common chronic degenerative disease caused by atherosclerosis.

Coronary artery bypass grafting (CABG) can effectively increase myocardial blood supply, prevent myocardial infarction, and improve quality of life (Liu et al., 2005). However, new-onset atrial fibrillation is a common complication after CABG, with an incidence rate of 30%. It induces hemodynamic instability, are often accompanied by left-ventricular systolic dysfunction and congestive heart failure, and increases the risk of stroke.

Several studies have shown that the initiation and maintenance of atrial fibrillation are strongly associated with inflammation (Marcus et al., 2008; Ederhy et al., 2012; Pilatis et al., 2013; Wu et al., 2013), which affects the electrical and structural remodeling of the heart (Huang et al., 2012). The role of C-reactive protein (CRP), a marker of inflammation, has been widely investigated. CRP is a non-specific acute-phase protein, and is elevated in many cardiovascular diseases, including coronary atherosclerotic heart disease, heart failure and hypertension. Elevated CRP levels are not only associated with simple and post-surgical atrial fibrillation, but also with cardioversion and recurrence of atrial fibrillation after ablation (Wu et al., 2013). However, there is no elevation of CRP levels in lone atrial fibrillation, indicating that inflammation is associated with cardiovascular disease, but not with atrial fibrillation per se (Ellinor et al., 2006a). One of the aims of the present study is to determine how CRP levels in patients with new-onset atrial fibrillation change after CABG.

Apelin has anti-inflammatory effects in different tissues (Pan et al., 2010; Visser et al., 2010; Lim et al., 2013). Ellinor et al. (2006b) showed that levels of apelin-12 were remarkably low in patients with atrial fibrillation. Recurrence of atrial fibrillation is high in patients with persistent atrial fibrillation and low apelin-12 levels after electrical cardioversion (Falcone et al., 2010).

Apelin is an endogenous ligand of the G-protein coupled receptor APJ, and exhibits homology to angiotensin II. The signaling system stimulated by apelin regulates many physiological functions and pathological processes (Lv et al., 2013). The main target of apelin is the cardiovascular system; it dilates blood vessels, and has antifibrotic and positive inotropic effects. Falcone et al. (2010) showed that the risk of recurrence of atrial fibrillation was 3.1 times greater in patients with low apelin levels than those with high apelin levels. Furthermore, Yang et al. (2014) concluded that apelin levels were lower in patients with different types of atrial fibrillation than in controls, indicating that apelin might contribute to the initiation and maintenance of atrial fibrillation.

We carried out a literature search on the Web of Science and ClinicalTrials.gov, using the search terms "apelin", "coronary artery bypass", and "atrial fibrillation". We also searched the Wanfang Database and China National Knowledge Infrastructure, using the terms "apelin", "coronary atherosclerotic heart disease", "surgery", and "atrial fibrillation"; or "apelin", "coronary atherosclerotic heart disease", "coronary artery bypass grafting", and "atrial fibrillation". However, we found no clinical studies of the relationship between apelin and atrial fibrillation after CABG. We therefore designed the present study to investigate this relationship.

In the cohort study, patients with coronary atherosclerotic heart disease scheduled to undergo CABG will be assigned to high and low apelin groups, according to preoperative apelin levels. The incidence of atrial fibrillation will be compared between the two groups 7 days postoperatively. In addition, a case-control trial in the same patients will compare plasma apelin levels and inflammatory response between those patients with and without atrial fibrillation 7 days postoperatively.


  Methods/Design Top


Study design

A prospective cohort study and retrospective case-control clinical trial.

Study setting

Department of Cardiac Surgery, General Hospital of Shenyang Military Region, Shenyang, China.

Study procedure

We will recruit patients with coronary atherosclerotic heart disease, without a history of atrial fibrillation, and scheduled to undergo CABG. Their baseline data will be assessed according to inclusion and exclusion criteria. Up to 120 eligible patients will be included after obtaining signed informed consent.

Preoperative plasma apelin levels will be measured, and patients will be allocated to high and low apelin groups. A cohort study will compare the incidence of new-onset atrial fibrillation in the high and low apelin groups 7 days postoperatively.

The same patients will then participate in a case-control study. Those patients with atrial fibrillation will comprise the atrial fibrillation group, and those without atrial fibrillation will be considered the non-atrial fibrillation group. Seven days postoperatively, levels of plasma apelin, brain natriuretic peptide, and hypersensitive CRP will be measured, and cardiac MRI will be used to evaluate fibrosis of the left and right atrium and pulmonary veins. MRI findings and plasma protein levels will be compared between the two groups. In addition, a heart auricle biopsy will be performed during the surgery for hematoxylin-eosin and Masson staining ([Figure 1]).
Figure 1: Trial protocol flow chart.

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Study participants

Up to 120 patients with coronary atherosclerotic heart disease scheduled to undergo CABG will be recruited from the Department of Cardiac Surgery, General Hospital of Shenyang Military Region, China.

Inclusion criteria


Patients will be considered for admission to the trial if they:

  • Meet WHO diagnostic criteria for coronary atherosclerotic heart disease
  • Are scheduled to undergo CABG
  • Have no history of atrial fibrillation
  • Have no history of thoracotomy
  • Provide written informed consent, having understood the benefits and risks of participation in the trial


Exclusion criteria

Patients meeting any of the following criteria will be excluded from the trial:

  • Valvular heart disease requiring surgical treatment
  • Severe cerebrovascular disease
  • Malignant tumor
  • Severe autoimmune disease
  • Thyroid dysfunction
  • Severe infection
  • Heart failure or acute myocardial infarction in the past month
  • Severe dysfunction of the heart, liver or lung
  • Refusal to cooperate with specimen collection and laboratory examination
  • Ongoing participation in other clinical trials
  • Unable to provide informed consent owing to mental disorders or language barriers


Assignment

In the cohort study, preoperative apelin levels will be measured and patients will be assigned to two groups accordingly: high apelin (> 250 pg/mL) and low apelin (≤ 250 pg/mL). In the case-control trial, patients with or without atrial fibrillation 7 days after surgery will be assigned to an atrial fibrillation group and a non-atrial fibrillation group, respectively.

Blinding


Surgeons and patients will not be blinded to group assignment. However, all data will be analyzed by an investigator using the blind method.

Sample size calculation

Incidence rates of postoperative atrial fibrillation in patients with high and low apelin levels are assumed to be 22% and 28%, respectively, in accordance with previous studies (Sun et al., 2009; Yu et al., 2015). Sample size will be calculated by tests of two proportions using Power Analysis and Sample Size (PASS) 11.0 software. Using class I error probability, α = 0.05 will be considered statistically significant; 1−β = 0.9 and β = 0.1. The final effective sample size will be 50 patients in each group; 120 samples will be included in this trial, and data will be subjected to intention-to-treat analysis.

Recruitment

When a patient is referred for CABG, his/her physician will inform him/her of the relevant aspects of this clinical trial, and provide contact details for participation. Patients interested in participation will contact staff responsible for the trial via telephone, e-mail or WeChat.

Determination of indicators

Plasma apelin, brain natriuretic peptide, high-sensitivity CRP


Fasting venous blood samples (5 mL) will be collected from the elbow of subjects in the morning, and centrifuged at 3,000 r/min for 10 minutes. Plasma will be harvested and stored at −80°C for further use. Plasma apelin and brain natriuretic peptide levels will be measured with a kit (Shanghai Ruicong Biotechnology Co., Ltd., Shanghai, China) using an enzyme-linked immunosorbent assay (Yang et al., 2014). High-sensitivity CRP levels will be determined by latex-enhanced immunoturbidimetric assay (Li, 2011). All measurements will be performed in the Clinical Laboratory of the General Hospital of Shenyang Military Region. All samples will be tested twice, and the average calculated.

Cardiac MRI

MRI will be performed using a Magnetom Avanto 1.5 T system (Siemens, Erlangen, Germany) (Zhao et al., 2005). Morphological structure of the heart and great vessels will be observed with half-Fourier acquisition single-shot turbo spin-echo sequences. Images will be collected in the end-diastolic phase of each cardiac cycle. Scanning parameters: repetition time, 700 ms; echo time, 26 ms; thickness, 4-8 mm; field of view, 340 × 340 mm to 450 × 450 mm.

Contrast-enhanced MRI of the aorta

A bolus injection of gadolinium diethylenetriaminepentaacetic acid will be administered at a rate of 3 mL/s (total, 2 mL); physiological saline will be infused at the same speed (total, 15-20 mL). The plane of interest will be the thoracic aorta at the level of the diaphragm, and aortic peak velocity will be measured. Scan delay time will be calculated after the peak filling rate is obtained. Contrast-enhanced and non-contrast-enhanced fast three-dimensional gradient-echo sequences will be used with the following scanning parameters: repetition time, 2.6 ms; echo time, 1.1 ms; thickness, 1 mm; field of view, 350 × 350 mm to 500 × 500 mm. After post-processing subtraction, maximum intensity projection and multiplanar reconstruction imaging will be performed.

All MRI images will be evaluated by two physicians (blinded to patients' data) from the MRI Room of the General Hospital of Shenyang Military Region. In the event of inconsistent assessments, images will be assessed by a third physician and the results consistent between two of the three physicians will be used.

Outcome measures

Primary outcomes


  • Incidence of new-onset atrial fibrillation 7 days after CABG in the high apelin and low apelin groups.
  • Plasma apelin levels 7 days after surgery. Apelin levels in circulating blood are associated with those in the cardiac atrium. Apelin is a cardiovascular polypeptide. The apelin receptor inhibits the angiotensin receptor, and is a protective factor against cardiovascular disease (Yu et al., 2014).


Secondary outcomes

  • Plasma brain natriuretic peptide level 7 days after surgery. Atrial fibrillation can cause a marked increase in serum brain natriuretic peptide (Tops et al., 2006). Brain natriuretic peptide participates in the onset of atrial fibrillation (Hoit, 2005) and can be used to predict its occurrence.
  • Plasma high-sensitivity CRP level 7 days postoperatively. High-sensitivity CRP is a non-specific acute-phase reactive protein, and its levels are elevated in patients with coronary atherosclerotic heart disease, indicating involvement of the inflammatory response (Hou et al., 2015).
  • Degree of fibrosis of the left and right atrium and pulmonary veins 7 days after CABG.


Baseline data of patients are shown in [Table 1] .
Table 1: Baseline patient data

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The schedule for outcome assessment is listed in [Table 2].
Table 2: Timing of outcome measures

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Adverse events

Adverse events after CABG will be recorded. These might include myocardial infarction, myocardial ischemia, bradycardia, hypotension, and stent thrombosis. We will provide a detailed record of date of onset, treatment-related processing method, and possible relationship with treatment. All adverse reactions should be reported to the researcher in charge and Clinical Institutional Review Board within 24 hours.

Data collection, management, analysis and open access

Data collection: A table will be formulated for data collection according to the trial design. Data will be added to an electronic database using a double data entry strategy.

Data management: Accuracy of information will be checked when all recruited patients are followed up. The database will be locked by the researcher in charge and will not be altered. All information relating to this trial will be preserved by The General Hospital of Shenyang Military Region, China.

Data analysis: The electronic database will be fully disclosed to a statistician for statistical analysis.

Open access: Published data will be available at http://www.figshare.com.

Statistical analysis

Statistical analysis will be performed by a statistician blinded to group assignment, using SPSS 19.0 software. If measurement data are normally distributed, data will be expressed as mean ± SD, and count data will be expressed as percentages. P < 0.05 will be considered statistically significant.

In the cohort study, the chi-square test will be used to compare the incidence rate of new-onset atrial fibrillation after CABG in patients with high and low apelin levels.

In the case-control study, paired t-tests will be used to compare plasma apelin, brain natriuretic peptide, and high-sensitivity CRP levels in patients with and without atrial fibrillation. Multivariate logistic regression analysis will be applied to determine the relationship between plasma apelin levels, cardiac fibrosis and inflammatory response with atrial fibrillation after CABG.

Auditing

Trial progression will be reported to the Ethics Committee of the General Hospital of Shenyang Military Region every month and the trial's status will be updated in the registration database.

Confidentiality


Test data, including medical records, will be saved electronically and in hard copy. The electronic data will be preserved in a dedicated password-protected computer and managed by a data manager. The paper data will be preserved in a secure, locked place by the data manager and researcher in charge for future viewing.


  Discussion Top


To our knowledge, there are no reports addressing the relationship between apelin and new-onset atrial fibrillation after CABG or the underlying mechanisms. This prospective cohort study and retrospective case-control study aims to fill this gap and determine whether apelin can be used as an indicator to predict atrial fibrillation after CABG. An indicator such as this would provide an objective basis for the clinical selection of a preventive intervention program for atrial fibrillation, and reduce or eliminate the occurrence of complications such as heart failure and embolism.

Trial status


Recruitment of patients at the time of submission[22]

 
  References Top

1.
Ederhy S, Di Angelantonio E, Dufaitre G, Meuleman C, Masliah J, Boyer-Chatenet L, Boccara F, Cohen A (2012) C-reactive protein and transesophageal echocardiographic markers of thromboembolism in patients with atrial fibrillation. Int J Cardiol 159:40-46.   Back to cited text no. 1
    
2.
Ellinor PT, Low A, Patton KK, Shea MA, MacRae CA (2006a) C-Reactive protein in lone atrial fibrillation. Am J Cardiol 97:1346-1350.   Back to cited text no. 2
    
3.
Ellinor PT, Low AF, Macrae CA (2006b) Reduced apelin levels in lone atrial fibrillation. Eur Heart J 27:222-226.   Back to cited text no. 3
    
4.
Falcone C, Buzzi MP, D′Angelo A, Schirinzi S, Falcone R, Rordorf R, Capettini AC, Landolina M, Storti C, Pelissero G (2010) Apelin plasma levels predict arrhythmia recurrence in patients with persistent atrial fibrillation. Int J Immunopathol Pharmacol 23:917-925.  Back to cited text no. 4
    
5.
Hoit BD (2005) Assessing atrial mechanical remodeling and its consequences. Circulation 112:304-306.   Back to cited text no. 5
    
6.
Hou P, Wang HS, Han JS, Chen ZH, Xu S, Liu Y (2015) Relationship between serum apelin level and inflammation in patients with atrial fibrillation. Zhongguo Xiongxin Xueguan Waike Linchuang Zazhi 22:976-979.  Back to cited text no. 6
    
7.
Huang CX, Zhang P, Ma CS, Yang YZ, Huang DJ, Cao KJ, Jiang H, Yang XC, Wu SL, Shang LH, Hua W, Zhang KJ, Li L, Ding YS, Ma J, Wang ZL, Liu SW, Liu X, Dong JZ, Yao Y, et al. (2012)Current knowledge and management recommendations of artrial fibrillation-2012. Zhonghua Xinlv Shichang Xue Zazhi 16:246-249.  Back to cited text no. 7
    
8.
Li QY (2011) Relationship of apelin with coronary artery disease and hypersensitive C-reactive protein. Nanjing, China: Southeast University.   Back to cited text no. 8
    
9.
Lim R, Barker G, Riley C, Lappas M (2013) Apelin is decreased with human preterm and term labor and regulates prolabor mediators in human primary amnion cells. Reprod Sci 20:957-967.   Back to cited text no. 9
    
10.
Liu G, Jin XX, Chen Y, Chen SL, Wan F, Jie JY (2005) Analysis of atrial fibrillation undergoing off pump coronary artery bypass graft surgery. Linchuang Xindian Xue Zazhi 24:26-29.  Back to cited text no. 10
    
11.
Lv D, Li H, Chen L (2013) Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis. Acta Biochim Biophys Sin (Shanghai) 45:527-533.  Back to cited text no. 11
    
12.
Marcus GM, Whooley MA, Glidden DV, Pawlikowska L, Zaroff JG, Olgin JE (2008) Interleukin-6 and atrial fibrillation in patients with coronary artery disease: data from the Heart and Soul Study. Am Heart J 155:303-309.   Back to cited text no. 12
    
13.
Pan CS, Teng X, Zhang J, Cai Y, Zhao J, Wu W, Wang X, Tang CS, Qi YF (2010) Apelin antagonizes myocardial impairment in sepsis. J Card Fail 16:609-617.  Back to cited text no. 13
    
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Pilatis ND, Anyfantakis ZA, Spiliopoulos K, Degiannis D, Chaidaroglou A, Vergou G, Kimpouri K, Cokkinos DV (2013) The role of BNP and CRP in predicting the development of atrial fibrillation in patients undergoing isolated coronary artery bypass surgery. ISRN Cardiol 2013:235018.  Back to cited text no. 14
    
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Sun DM, Zheng R, Yang KM, Yuan X, Zhang SJ, Li Y, Wang Q, Tang Y, Sun HS, Song YH, Wang LQ, Wei H, Fan HG, Liu LQ (2009) Impaired myocardiu GLUT3 levels associated with the risk of new-onset atrial fibrillation after isolated coronary artery bypass grafting surgery. Zhongguo Fenzi Xinzang Bingxue Zazhi 9:161-163.  Back to cited text no. 15
    
16.
Tops LF, Bax JJ, Zeppenfeld K, Jongbloed MR, van der Wall EE, Schalij MJ (2006) Effect of radiofrequency catheter ablation for atrial fibrillation on left atrial cavity size. Am J Cardiol 97:1220-1222.  Back to cited text no. 16
    
17.
Visser YP, Walther FJ, Laghmani el H, Laarse Av, Wagenaar GT (2010) Apelin attenuates hyperoxic lung and heart injury in neonatal rats. Am J Respir Crit Care Med 182:1239-1250.   Back to cited text no. 17
    
18.
Wu N, Xu B, Xiang Y, Wu L, Zhang Y, Ma X, Tong S, Shu M, Song Z, Li Y, Zhong L (2013) Association of inflammatory factors with occurrence and recurrence of atrial fibrillation: a meta-analysis. Int J Cardiol 169:62-72.   Back to cited text no. 18
    
19.
Yang SH, Liu YB, Han ML, Wang C, Liu Z (2014) Level of plasma apelin and its significance in patients with different types of atrial fibrillation. Jiangsu Shiyong Xindianxue Zazhi 23:249-252.  Back to cited text no. 19
    
20.
Yu GJ, Yan F, Zhu T, Liu Z, Huo Q (2015) Atrial fibrillation in the elderly old patients who underwent off-pump coronary artery bypass grafts surgery. Zhongguo Xinxueguan Zazhi 20:136-140.  Back to cited text no. 20
    
21.
Yu XH, Tang ZB, Liu LJ, Qian H, Tang SL, Zhang DW, Tian GP, Tang CK (2014) Apelin and its receptor APJ in cardiovascular diseases. Clin Chim Acta 428:1-8.  Back to cited text no. 21
    
22.
Zhao SH, Lu MJ, Zhang Y, Jiang SL, Huang LJ, Wang HY, Wu YL, Du MJ, Liu YQ (2005) Clinical application for cardiovascular diseases using 1.5T senior MR. Zhonghua Fangshexue Zazhi 39:577-581.  Back to cited text no. 22
    


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    Tables

  [Table 1], [Table 2]



 

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