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Role of tumor necrosis factor-alpha in the pathogenesis of atrial fibrillation

DENG, Hai; XUE, Yu-mei; ZHAN, Xian-zhang; LIAO, Hong-tao; GUO, Hui-ming; WU, Shu-lin

doi: 10.3760/cma.j.issn.0366-6999.2011.13.010
Original article
Free
SDC

Background Tumor necrosis factor-alpha (TNF-α) is a pleiotropic proinflammatory cytokine and contributes to many kinds of cardiovascular diseases via its receptors (TNFR1/TNFR2). We hypothesize that TNF-α plays a role in the pathogenesis of chronic atrial fibrillation (AF).

Methods Sixty-seven consecutive patients who were scheduled to have cardiac surgery were enrolled into the study. Thirty-one patients with rheumatic heart disease (RHD) and AF were enrolled as study group (AF group). The sinus rhythm (SR) control groups consisted of 20 patients with RHD and 16 patients with coronary artery disease (CAD). Peripheral blood sample was collected before the operation. About 5 mm3 left atrial tissue was disserted during the operation and was separated into three parts for Western blotting, real time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) analysis.

Results Compared with the controls (RHD SR and CAD SR), the levels of TNF-α ((14.40±5.45) pg/ml vs. (4.20±3.19) pg/ml vs. (2.68±2.20) pg/ml, P=0.000) and its soluble receptor 1 (sTNFR1) ((1623.9±558.6) pg/ml vs. (1222.3±175.6) pg/ml vs. (1387.5±362.2) pg/ml, P=0.001) in plasma were higher in patients with AF. TNF-α level had positive correlation with the left atrial diameter (LAD) (r=0.642, P=0.000). Western blotting analysis showed that the protein levels of TNF-α (0.618±0.236 vs. 0.234±0.178 vs. 0.180±0.103, P=0.000) were higher in patients with AF. The RT-PCR analysis results demonstrated that the mRNA expression of TNF-α (0.103±0.047 vs. 0.031±0.027 vs. 0.023±0.018, P=0.000) increased in patients with AF. IHC analysis displayed that, comparing to the SR, the expression of TNF-α (0.125±0.025 vs. 0.080±0.027 vs. 0.070±0.023, P=0.000) increased in the AF group. The protein level and mRNA expression of TNF-α also had positive correlation with left atrium diameter (LAD) (r=0.415, P=0.000 and r=0.499, P=0.000).

Conclusions The results revealed that TNF-α elevated in the plasma and left atrial tissue and had positive correlation with LAD in patients of chronic AF. TNF-α might involve in the pathogenesis of chronic AF.

Chin Med J 2011;124(13):1976–1982

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China (Deng H, Xue YM, Zhan XZ, Liao HT, Guo HM and Wu SL)

Correspondence to: WU Shu-lin, Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China (Tel: 86–20–83826001. Fax: 86–20–83875453. Email: wushulin8888@yahoo.com.cn) This work was supported by Province Science and Technological Program of Guangdong (No. 2010B060900018) and Province Natural Science Foundation of Guangdong (No. 1015008002000010).

Conflict of interests: none.

(Received March 25, 2011)

Edited by WANG Mou-yue

Atrial fibrillation (AF) is one of the most common arrhythmia which has high mortal and disable rate.1 Thus, to elucidate the complexities of AF pathogenesis and perpetuation provides a great hope of developing future novel and effective therapeutic strategies. Inflammation has been postulated as a predisposing factor for AF and its complications, including thromboembolism.1 After the first time Frustaci et al2 demonstrated evidence of focal myocarditis on three out of 14 patients with lone AF, increasing evidences derived from studies investigating the link between AF and circulating inflammatory markers such as high sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, white cells counting and tumor necrosis factor alpha (TNF-α) have been found to support that inflammation was associated with the pathological process of AF.1

CRP is the archetypal non-specific downstream marker of inflammation, which is produced by the liver in response to IL-6 and TNF-α. Increasing hs-CRP levels have been shown to be an independent risk factor for future AF among patients without a previous AF history in sinus rhythm (SR).3,4 Pre-electrical cardioversion (EC) hs-CRP levels have been noted to be an independent predictor of both initial5 and subsequent6 EC success, as well as the clinical burden of AF.7 TNF-α is one of the upstream cytokine appears in the early stage of inflammatory which also stimulates the production of other cytokines such as IL-6, IL-1 and acute phase protein like CRP afterwards.8 TNF-α is mainly secreted by monocytes and macrophages and plays an important role in the activation of immune system. It is released in the circulation under stimulation of many factors including IL-1b and bacterial endotoxin. Most of the cardiac diseases themselves have pro-inflammatory effect. TNF-α is a kind of pleiotropic pro-inflammatory factor and the expression is upregulated in many cardiovascular diseases such as dilated cardiomyopathy, acute myocarditis, graft rejection, myocardial infarction (MI) and congestive heart failure.9 Local concentration of TNF-α elevating should induce vessel inflammatory reaction and damage the diastolic function of the endothelial cells. Results on whether or not TNF-α was related to the pathogenesis and perpetuation of AF were conflicting.10,11 In this study, plasma level, protein content and mRNA expression of TNF-α in 31 patients with chronic AF were detected and compared with the sinus ones. We hypothesized that TNF-α should play a role in chronic AF by combining research in both plasma and tissue samples.

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METHODS

Patient enrollment

Sixty-seven consecutive patients who were going to undertake cardiac surgery were prospectively enrolled in this study. Thirty-one subjects with rheumatic heart disease (RHD) and chronic AF were enrolled as study group (AF group), while twenty subjects with RHD only and sixteen with coronary artery disease (CAD) were enrolled as the control group. The subjects were considered eligible to be enrolled into the AF group if they had obvious AF history and had been documented by electrocardiogram with AF for more 48 hours. The control group consisted of consecutive patients in sinus rhythm and no history of AF. Subjects with liver or renal failure, dropsical nephritis, diabetes, hyperthyroidism, hypertension, cardiomyopathy, autoimmune disease, rheumatic fever in active stage, heart failure over New York Heart Association (NYHA) III or left ventricular ejection fraction (LVEF) less than 40%, infectious history and other heart diseases were excluded from participation in the study. None of the subjects had taken anti-inflammatory drugs previously more than two weeks before the study. All patients had a three-month follow-up after the surgery. Written informed consent was obtained from every patient after a full explanation of the research. The study was approved by the Ethics Committee of Guangdong General Hospital.

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Data collecting

Baseline demographics, physical examination, routine laboratory testing, 24 hours electrocardiogram (Holter), echocardiography, and additional clinical data were available for all patients before and three months after the surgery. The presence or the absence of AF was determined by the Holter and history of AF for the patients. The echocardiographic data included LVEF and left atrial diameter (LAD).

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Blood collection and measurement

Blood samples were obtained from the elbow vein around 8 a.m. after an overnight fasting before and three months after the surgery. After staying in the room temperature for 1 hour, serum was obtained by centrifugation at 2 000 ×g at 4°C for 10 minutes. The serum was stored at -70°C until assayed. The concentrations of plasma TNF-α, sTNFR1 and IL-6 were measured by ELISA.12 The ELISA sets were obtained from R&D, Inc. USA for the measurement of three cytokines. Cytokine levels in each sample were calculated by reference to a concentration of the sample used and determined by using Bradford assay, with bovine serum albumin as the standard. All procedures were strictly followed the instruction of the ELISA sets. High-sensitive C-reactive protein (hsCRP) was assayed with latex-enhanced immunonephelometry on a Behring BN-ProSpec Nephelometer (Dade Behring, Marburg, Germany) in the clinical laboratory of the hospital.

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Tissue collection

Left auricular appendage (LAA) tissue (0.3–0.5 mm3) was disserted during the surgery. Each piece of tissue was cut immediately into three parts. One was dropped into liquid nitrogen and then stored in the -80°C for protein extraction. Another was dropped into an EP tube containing RNAstore Reagent (TIANGEN Biotech, China) and then stored in -80°C for RNA isolation. The third was stored in 4% neutral formaldehyde methanal in 4°C over night. Because the off pump coronary artery bypass grafting (CABG) was operated on the CAD subjects, little tissue could be cut in the surgery. The tissue from CAD subjects was only used for protein and RNA detection.

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Western blotting analysis

Protein extraction of part of LAAs from patients was followed by the instruction of the total protein extraction kit (Applygen Technologies Inc, China). Protein concentration was determined using the DC assay (Bio-Rad, USA) with a bovine albumin standard. Protein levels of TNF-α were determined by Western blotting and expressed as ratio to levels of reduced glyceraldehyde-phosphate dehydrogenase (GAPDH).12 Denatured protein (10 μg) was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes (Stratagene, USA) followed by staining with Ponceau S solution (Sigma, USA). Membranes were incubated with primary antibody against GAPDH (Affinit Reagents, USA), subunit of TNF-α (1:1000, Santa Cruz Biotechnology, USA). Horse radish peroxidase-conjugated rabbit anti-mouse or anti-rabbit IgG (1:5000, Santa Cruz Biotechnology) was used as secondary anti-body. Signals were detected by the ECL (Merck Millinpore, USA)-detection method (Amersham GE, USA) and quantified by densitometry. The amount of protein chosen was in the linear immunoreactive signal range. The immunoreactive singal was exposed in a film (Fuji, Japan) and analysed with gelpro analyzer after scanning. The specificity of the antibodies was checked by pre-incubation with control peptide antigen.

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Quantitative real-time polymerase chain reaction (PCR)

Total RNA was isolated from 100–300 mg atrial tissue samples with TRIzol (Invitrogen, USA), followed by chloroform extraction and isopropanol precipitation, Dnase treatment, and quality control with ployacrylamide gel electrophoresis. First-strand cDNA was synthesized from 2 μg of total RNA with High Capacity cDNA Archive Kits. Real-time quantitative PCR (Q-PCR) was performed with 6-carboxy-fluorescein-labeled fluorogenic TNF-α13 (S: 5′-AGTGAAGTGCTGGCAACCACTA-3′; A: 5′-CTCCGTGTCTCAAGGAAGTCTG-3′) and GAPDH (S: 5′-CACTGGCGTCTTCACCACCAT-3′; A: 5′-GTGCAGGAGGCATTGCTGAT-3′) TaqMan primers and probes and TaqMan universal master mix. Fluorescence signals were detected in duplicate, normalized to 18S ribosomal RNA, and quantified with BioRad IQ5 software (BioRad).

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Immunohistochemistry

Immunohistochemistry14 was performed in patients with RHD. Two groups of 5 μm thick frozen left LAA sections were made. Sections were air dried before use or immediately fixed for 10 minutes in 4% paraformaldehyde in phosphate buffered saline (PBS). After washing 3 times (PBS, 10 minutes each) and 30 minutes blocking with 1% BSA in PBS, sections were incubated with peroxidase conjugated goat-anti-rabbit IgG (Santa Cruz Biotechnology) (1 hour). Three washes with PBS were followed by one with aqua dest (5 minutes), peroxidase activity was detected using a buffer of 40 mg 3-amino-9-ethylcarbazole (Sigma), 10 ml N,N di-methylformamide (Merck, USA), hydrogen peroxide 0.01% (v/v) and 190 ml 0.05 mo/L sodium acetate (pH 4.95). After staining for 10 minutes, sections were rinsed with water, counterstained with haematoxylin (Sigma) and mounted with Kaiser's glycerol gelatin (Merck). The photos were observed under immunofluorescence microscope (Nikon D60, Japan). The results were analyzed by Image-Pro Plus 6.0.

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Statistical analysis

Continuous variables were defined as mean ± standard error if they were normally distributed or median values were represented. T-tests were used for normally distributed continuous variables and independently distributed samples. Groups for categorical variables were assessed by chi-square or Fisher's exact tests. Correlation coefficients were assessed between TNF-α and LAD, including the serum concentration, protein and mRNA expression of TNF-α. One-way analysis of variance (ANOVA) was used for three groups normally distributed continuous variables. A P value of 0.05 for two-tailed analysis was considered to be statistically significant. All statistical analysis was made by the SPSS 15.0 (SPSS Inc., USA).

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RESULTS

Clinical features

Patients’ characteristics are shown in Table 1. As a whole, most characteristics were similar among three groups. Variables RHD AF RHD SR CAD SR F/χ2 values P values However, the AF group had a larger LAD (P=0.0000; Table 1) than the control groups. All the patients with persistent AF recovered to sinus rhythm after the surgery but 7 of 31 (22.6%) recurred three months later. There were 2 patients separately in RHD SR (10%) and CAD SR (12.5%) group presented AF in the end of the follow up. Totally, 11 patients (16.4%) presented AF three months after the surgery. Compared to the patients maintaining sinus rhythm, patients with AF three months after the surgery had larger LAD (P=0.033; Table 2).

Table 1

Table 1

Table 2

Table 2

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Serum inflammatory biomarkers elevated in AF

The levels of TNF-α ((15.40±0.98), (4.20±0.71), (2.68±0.55) pg/ml, P=0.000; Figure 1A), hsCRP ((6.60±0.82), (2.91±0.73), (2.29±0.46) pg/ml, P=0.000; Figure 1A), IL-6 ((8.02±2.36), (2.44±0.54), (2.31±0.37) pg/ml, P=0.048; Figure 1A), and sTNFR1 ((1622.96±100.33), (1222.30±99.6), (1387.35±90.56) pg/ml, P=0.007; Figure 1B) were significantly higher in AF patients than in controls while using univariate analysis.

Figure 1.

Figure 1.

As shown in Figure 1C, TNF-α concentrations were positively correlated with LAD in all study subjects (r=0.545, P=0.000).

Patients recurred AF or occurred new AF events after the surgery had higher TNF-α, IL-6 and hsCRP levels (P <0.05; Table 2, Figure 1D).

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Tissue protein levels of TNF-α increased in AF

The expression of protein and mRNA level of TNF-α in atrial tissue of patients with AF was determined by Western blotting (Figure 2A) and Q-PCR respectively. Surprisingly, protein levels of TNF-α were significantly increased in patients with persistent AF compared to controls (0.618±0.236 vs. 0.234±0.178 vs. 0.180±0.103, P=0.000; Figure 2B), and the protein expression had positively correlation with LAD (r=0.415, P=0.000; Figure 2C). In parallel, the mRNA expression of TNF-α elevated in AF group compared to the control groups (0.103±0.047 vs. 0.031±0.027 vs. 0.023±0.018, P=0.000; Figure 3A), and had positively correlation with the LAD (r=0.499, P=0.000; Figure 3B). The GAPDH levels did not show significant difference among the groups (P >0.05).

Figure 2.

Figure 2.

Figure 3.

Figure 3.

Immunohistochemical localization of TNF-α was performed to determine the expression and activity of the protein. Staining intensity of the nucleus and cytoplasm in patients with persistent AF was more than that observed in patients with sinus rhythm (Figure 4A–D). IHC analysis showed that the protein expression of TNF-α was higher in AF patients compared to the sinus (P=0.000; Figure 4E).

Figure 4.

Figure 4.

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DISCUSSION

There is increasing evidence that AF is related to inflammation.2,15 TNF-α is one of the upstream cytokines which appears in the early stage of the inflammation and related to several cardiovascular diseases such as coronary artery disease, heart failure and myocarditis.9 Recent research also found that TNF-α elevated in the serum of patients with AF.10 To reveal the relation between TNF-α and AF, we studied the protein level and expression on both blood and left atrium tissue sample in patients with AF. Rheumatic heart disease relates to inflammation when being in the active stage of rheumatic fever. Though patients had normal antistrepholsin O (ASO) and erythrocyte sedimentation rate (ESR), we also enrolled 16 CAD patients as blank control to make the result more credible.

In the present study, the concentration of TNF-α elevated in AF patients and so were the hsCRP and IL-6. Corresponding to the result of serum sample, the protein and mRNA expression of TNF-α of left atrium tissue increased in AF patients too. TNF-α was strongly associated with AF. Evidence7 showed that hsCRP was the independent predictive factor of AF and early recurrence of AF after cardioversion. In the present study, TNF-α was found drifted accompanying by hsCRP. We supposed that inflammation was involved in AF from the early stage. These results suggest that inflammation may be related to “burden” of AF.7 Inflammation may be one of the reasons that cause AF burgeon AF.

Inflammation may lead to electrical and structural remodeling in atrial tissue.16,17 The fibrillating atria cause calcium accumulation within the atrial myocytes and then induce cells apoptosis. Loss of atrial myocytes is replaced by fibrous scar which contributes to the abnormal electrical conduction and spreading. The aberrant activity of atria could trigger a low-grade inflammatory response.16,17 Hack et al18 reported that inflammatory factors involved in the pathogenesis and progression of AF by activating complement system or oxidative stress. However, it is still difficult to tell which came first, the “chicken” or the “egg” at present.

TNF-α was found higher in patients with persistent AF than paroxysmal AF, followed by patients with sinus rhythm.10 The result was similar to ours and suggested the association between TNF-α and AF. On the contrary, Rizos et al reported11 that it was hsCRP but not TNF-α elevated in AF patients with hypertension. Short half-time of TNF-α may be the reason in different results.10,19 Furthermore, we also found soluble receptor 1 of TNF-α (sTNFR1) level elevated in the serum of patients with AF. sTNFR1 competitively elevated when the excretion of TNF-α increased, adjusting the action of TNF-α.20 Consistency of the result of two cytokines ulteriorly confirmed the elevation of TNF-α during the process of AF. Ascending of both TNF-α and sTNFR1 made the result much credible. TNF-α adjusts synthesis and metabolism of cells according to two different receptors, TNFR1 and TNFR2. As the result shown in the present study, we presumed that TNFR1 may be the main receptor which helped TNF-α in AF. The mechanism that TNF-α was involved in AF is still not clear. Nuclear factor kappaB (NF-κB) should take part in the transcriptional regulation of TNF-α.21 Qu et al22 reported that the expression of NF-κB increased in atrial tissue of RHD patients with AF, which was accompanying with the elevation of TNF-α in the serum. The results demonstrated that TNF-α may affect the transcription of atrial myocytes by the signal pathway of NF-κB to make AF develop and maintain. On the other hand, oxidative stress may be the main mechanism. TNF-α increased the product of oxidative stress in atrial myocytes, which made the glutathione of mitochondria exhausted, and then mitochondria swelling and disintegrating.23 TNF-α could inhibit the calcium current of ventricular myocytes of mouse but the inhibition decreased by acetylcysteine.24

Hs-CRP was found increased in patients with AF7,25 and was confirmed as predictor of early recurrence of AF after cardioversion.8,26 Interleukin-6 had pro-inflammatory and protective characteristic at the same time. But in most of researches in relation to AF, IL-6 was found elevated.27,28 Suggesting to the past research result, in the present study, hsCRP and IL-6 were found elevated in the serum of AF patients too. Moreover, 11 patients who were found had AF events three months after the surgery had higher hsCRP, IL-6 and TNF-α than those who remained sinus rhythm. These results suggested that inflammatory factors including TNF-α not only related to AF but also AF post surgery.

The present study demonstrated that no matter patients with AF before or post surgical operation had larger LAD than the sinus ones; protein level and expression of TNF-α were positively related to LAD. LAD is the mark of structural remolding in cardiac ultrasound and previous researchrd had shown that LAD related to the development and maintenance of AF.29,30 Enlarged left atrium induced volume and pressure overload and then made function failure and abnormal electrical activity.31 Structure remolding of the left atria triggered a local inflammatory response, leading to the maintaining of AF.5 Nevertheless, two atria may play different roles in AF. Right atrium might just be onlooker in AF32 but left atrium was considered as the main chamber to induce and maintain the post-surgical AF.33 Remolding of left atrium should be the substrate of AF. In the present study, the studied tissue was from left atrium which made the result much reliable. Protein and mRNA expression of TNF-α upregulated in the tissue of left atrium of patients with AF revealed that inflammation may get involved in the remolding of left atrium. TNF-α may participate in the process of atrial remodeling.

The main limitation of the study is that we did not make multivariate analysis so we could not determine if TNF-α was the most related factor to AF or AF after surgery. Because of the specimen collecting limitation, the number of subjects enrolled was quiet small. Finally, we compared TNF-α between patients with persistent AF and sinus rhythm and it would be much meaningful if a paroxysmal group enrolled.

In conclusion, the results demonstrate the association of the level and expression of TNF-α both in patients with AF. The study was carried on with human blood and tissue sample, so it may provide direct evidence that inflammation related to AF. It might provide insights into further mechanistic research and peculiar AF therapeutic targets. Nevertheless, the development of AF is a long term, multi-factorial and complicated process. We cannot tell whether TNF-α caused the disease or it was just one of the biomarkers of AF. The exact role of TNF-α in AF needs to be further studied.

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Keywords:

tumor necrosis factor alpha; atrial fibrillation; left atrial diameter

© 2011 Chinese Medical Association