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Autoantibodies against M2-muscarinic and β adrenergic receptors: New mediators in atrial fibrillation?
International Journal of Cardiology 197 (2015) 180–181
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Autoantibodies against M2-muscarinic and β adrenergic receptors: New mediators in atrial fibrillation? Bo He, Zhibing Lu, Wenbo He, Hong Jiang ⁎ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China Cardiovascular Research Institute of Wuhan University, PR China
a r t i c l e
i n f o
Article history: Received 27 April 2015 Received in revised form 3 June 2015 Accepted 21 June 2015 Available online 26 June 2015 Keywords: M2-muscarinic receptor autoantibody β adrenergic receptor autoantibody Atrial fibrillation
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinical practice. It has been shown that many factors are involved in the pathogenesis of AF, including electrical remodeling, structural remodeling, neural remodeling and inflammation [1,2]. A large number of evidence demonstrates that cardiac autonomic nervous system plays an important role in the initiation, the progression and the maintenance of AF [3–5]. Although the mechanisms of AF have been explored widely and deeply in past decades, there are still some AF patients in which the mechanism of AF is classified as “idiopathic”. Recently, emerging evidence suggested the autoimmune disorder as a possible underlying mechanism for AF. Activating autoantibodies that serve as agonists to the cardiac autonomic nervous system are shown to probably be involved in the development of AF [6,7]. It has been well known that the increase of vagal tone is a principal underlying mechanism of AF. As the M2 receptors mediate parasympathetic signaling in the heart, the autoantibodies against M2-muscarinic receptors (anti-M2-R) were naturally presumed to contribute to AF development. In a cohort of 104 patients with dilated cardiomyopathy, age-matched with 104 patients with idiopathic AF and 104 healthy controls, Baba et al. [8] found that patients with idiopathic AF had a markedly higher prevalence of anti-M2-R as compared to controls. Meanwhile, patients with dilated cardiomyopathy who had
⁎ Corresponding author at: Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan 430060, PR China. E-mail address: [email protected] (H. Jiang).
http://dx.doi.org/10.1016/j.ijcard.2015.06.066 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
documented AF had greater anti-M2-R level than patients who did not have AF. Similar results were also found by Yalcin et al. [9] in patients with lone paroxysmal AF in a recent study in which lone paroxysmal AF patients had significantly higher serum anti-M2-R level than healthy controls and the anti-M2-R level was an independent predictor for the presence of lone paroxysmal AF. In addition, pre-procedural anti-M2-R level was found to predict the recurrence of AF after catheter ablation. Zou et al. [10] reported 76 AF patients with preserved left ventricular systolic function who underwent radiofrequency catheter ablation. They showed that the frequency and titer of serum anti-M2-R in AF patients were significantly higher than those in the control group with sinus rhythm. The multivariate analysis showed that pre-procedural serum anti-M2-R was an independent predictor for the recurrence of AF at the time point of 12 months after ablation (odds ratio: 4.701; 95% confidence interval: 1.590–13.894; p = 0.005). Similar results were also found in paroxysmal AF patients who underwent cryoballoon-based pulmonary vein isolation [11], in which anti-M2-R levels of N277.65 ng/mL was an independent predictor of late AF recurrence. Furthermore, serum anti-M2-R levels were found to predict left atrial fibrosis severity in paroxysmal lone AF patients undergoing cryoablation [12], which may be helpful for selecting appropriate patients for ablation. To investigate the effect of anti-M2-R on atrial electrophysiology, Baba et al. [8] added patients' purified anti-M2-R to chick embryo and demonstrated that purified IgG from AF patients exhibited negative chronotropic effects and induced supraventricular arrhythmias. By using a rabbit model immunized with synthetic peptide corresponding to the M2 muscarinic receptor, Hong et al. [6] demonstrated that anti-M2-R positive rabbits showed a significantly shorter atrial effective refractory period and a longer intra-atrial activation time than control rabbits. M2-immunized rabbits also showed upregulated protein levels of M2 receptor and GIRK4 and upregulated mRNA levels of GIRK1 and GIRK4 (2 homologous genes of KACh). Histological examination revealed significantly increased diffuse fibrotic deposition in anti-M2-R positive rabbit atria compared with control rabbits. These results indicated that anti-M2-R may create arrhythmogenic substrate and participate in the initiation and perpetuation of AF. Besides anti-M2-R, the autoantibodies against the β adrenergic receptors (anti-β-R) were also implicated in promoting the development of AF. In patients with hyperthyroidism, the patients with AF were more likely to have anti-β1-R, as compared to patients without AF [13]. The mean anti-β-R activity was also significantly higher in patients with
Letter to the Editor
AF than those with sinus rhythm [14]. In patients with lone paroxysmal AF, serum anti-β1-R level was significantly higher than healthy controls and the anti-β1-R level was an independent predictor for the presence of lone paroxysmal AF [9]. Just as serum anti-M2-R level plays a predictive role in AF recurrence after catheter ablation, pre-procedural serum anti-β1-R level was also an independent predictor of late AF recurrence following cryoablation in paroxysmal AF patients [11]. In isolated canine pulmonary veins, Stavrakis et al. [13] showed that IgG from anti-β1-R positive patients induced hyperpolarization, decreased action potential duration, enhanced early after depolarizations and facilitated triggered activity. Additionally, anti-β2-R was found to promote atrial arrhythmia vulnerability in a recent study by Li et al. [15]. In 5 rabbits pre- and postimmunization for anti-β2-R, burst atrial pacing was performed before and after the infusion of acetylcholine in incremental concentrations to induce atrial arrhythmias. The results showed that rabbits postimmunization had significantly more episodes of atrial arrhythmias (including AF) when compared to that of preimmunization. Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of β-2 adrenergic receptor in transfected cells in vitro compared to the preimmune sera. Although the cumulative and emerging evidence reveals that the activation of autoantibodies targeting M2-muscarinic and β adrenergic receptors may be contributory or even causal to AF pathogenesis, whether these autoantibodies promote AF, or they are just AF biomarkers or bystanders has always been the focus of controversy [16–19]. Even though experimental studies have demonstrated that the anti-M2-R or anti-β-R was able to induce atrial structural remodeling and electrophysiological remodeling, the underlying molecular mechanisms are still unclear. Meanwhile, the pathophysiology of AF in human is more complex than that in animal models as AF has heterogeneous phenotypes and often coexists in many other diseases. It is probable that these antibodies are both biomarkers and pathophysiological mediators. Further studies are warranted to clarify these issues. Nevertheless, current available researches did offer us a novel etiologic and mechanistic insight into AF. If the causal relationship between anti-M2-R or anti-β-R and AF was confirmed and the detailed mechanisms were illuminated by further clinical and experimental studies, strategies targeting the corresponding pathogenic autoantibodies may be a promising alternative intervention in AF treatment. Conflicts of interest None. Acknowledgment This work was supported by grants 81300181 (BH), 81370281 (ZL) and 81400254 (WH) from the National Natural Science Foundation of China.
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References [1] A. Kourliouros, I. Savelieva, A. Kiotsekoglou, M. Jahangiri, J. Camm, Current concepts in the pathogenesis of atrial fibrillation, Am. Heart J. 157 (2009) 243–252. [2] U. Schotten, S. Verheule, P. Kirchhof, A. Goette, Pathophysiological mechanisms of atrial fibrillation: a translational appraisal, Physiol. Rev. 91 (2011) 265–325. [3] Z. Lu, B.J. Scherlag, J. Lin, L. Yu, J.H. Guo, G. Niu, et al., Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi, Cardiovasc. Res. 84 (2009) 245–252. [4] Z. Lu, B.J. Scherlag, J. Lin, G. Niu, K.M. Fung, L. Zhao, et al., Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing, Circ. Arrhythm. Electrophysiol. 1 (2008) 184–192. [5] L. Yu, B.J. Scherlag, Y. Sha, S. Li, T. Sharma, H. Nakagawa, et al., Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle, Heart Rhythm. 9 (2012) 804–809. [6] C.M. Hong, Q.S. Zheng, X.T. Liu, F.J. Shang, H.T. Wang, W.R. Jiang, Effects of autoantibodies against M2 muscarinic acetylcholine receptors on rabbit atria in vivo, Cardiology 112 (2009) 180–187. [7] H.C. Lee, K.T. Huang, X.L. Wang, W.K. Shen, Autoantibodies and cardiac arrhythmias, Heart Rhythm. 8 (2011) 1788–1795. [8] A. Baba, T. Yoshikawa, Y. Fukuda, T. Sugiyama, M. Shimada, M. Akaishi, et al., Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy, Eur. Heart J. 25 (2004) 1108–1115. [9] M.U. Yalcin, K.M. Gurses, D. Kocyigit, S.A. Kesikli, A.H. Ates, B. Evranos, et al., Elevated M2-muscarinic and β1-adrenergic receptor autoantibody levels are associated with paroxysmal atrial fibrillation, Clin. Res. Cardiol. 104 (2015) 226–233. [10] C. Zou, Z. Zhang, W. Zhao, G. Li, G. Ma, X. Yang, et al., Predictive value of preprocedural autoantibodies against M2-muscarinic acetylcholine receptor for recurrence of atrial fibrillation one year after radiofrequency catheter ablation, J. Transl. Med. 11 (2013) 7. [11] M.U. Yalcin, K.M. Gurses, D. Kocyigit, S.A. Kesikli, M. Dural, B. Evranos, et al., Cardiac autoantibody levels predict recurrence following cryoballoon-based pulmonary vein isolation in paroxysmal atrial fibrillation patients, J. Cardiovasc. Electrophysiol. (2015), http://dx.doi.org/10.1111/jce.12665. [12] K.M. Gurses, M.U. Yalcin, D. Kocyigit, S.A. Kesikli, U. Canpolat, H. Yorgun, et al., M2-muscarinic acetylcholine receptor autoantibody levels predict left atrial fibrosis severity in paroxysmal lone atrial fibrillation patients undergoing cryoablation, Europace 17 (2015) 239–246. [13] S. Stavrakis, X. Yu, E. Patterson, S. Huang, S.R. Hamlett, L. Chalmers, et al., Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism, J. Am. Coll. Cardiol. 54 (2009) 1309–1316. [14] A. Galloway, H. Li, M. Vanderlinde-Wood, M. Khan, A. Benbrook, C. Liles, et al., Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism, Endocrine (2014), http://dx.doi.org/10.1007/s12020-014-0495-4. [15] H. Li, B.J. Scherlag, D.C. Kem, C. Zillner, S. Male, S. Thirunavukkarasu, et al., Atrial tachycardia provoked in the presence of activating autoantibodies to β2adrenergic receptor in the rabbit, Heart Rhythm. 10 (2013) 436–441. [16] L.J. Field, Lone atrial fibrillation and autoantibodies: cause versus effect, J. Cardiovasc. Electrophysiol. 9 (1998) 618–619. [17] D. Dobrev, T. Christ, U. Ravens, Muscarinic subtype-2 receptor autoantibodies: actors or bystanders in human atrial fibrillation? Eur. Heart J. 25 (2004) 1091–1092. [18] A. Baba, M. Fu, Autoantibodies in atrial fibrillation: actor, biomaker or bystander? Autoimmunity 41 (2008) 470–472. [19] M. Fu, Autoantibodies in atrial fibrillation: actors, biomarkers or bystanders? How far have we come? Cardiology 112 (2009) 178–179.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Autoantibodies against M2-muscarinic and β adrenergic receptors: New mediators in atrial fibrillation? Bo He, Zhibing Lu, Wenbo He, Hong Jiang ⁎ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China Cardiovascular Research Institute of Wuhan University, PR China
a r t i c l e
i n f o
Article history: Received 27 April 2015 Received in revised form 3 June 2015 Accepted 21 June 2015 Available online 26 June 2015 Keywords: M2-muscarinic receptor autoantibody β adrenergic receptor autoantibody Atrial fibrillation
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinical practice. It has been shown that many factors are involved in the pathogenesis of AF, including electrical remodeling, structural remodeling, neural remodeling and inflammation [1,2]. A large number of evidence demonstrates that cardiac autonomic nervous system plays an important role in the initiation, the progression and the maintenance of AF [3–5]. Although the mechanisms of AF have been explored widely and deeply in past decades, there are still some AF patients in which the mechanism of AF is classified as “idiopathic”. Recently, emerging evidence suggested the autoimmune disorder as a possible underlying mechanism for AF. Activating autoantibodies that serve as agonists to the cardiac autonomic nervous system are shown to probably be involved in the development of AF [6,7]. It has been well known that the increase of vagal tone is a principal underlying mechanism of AF. As the M2 receptors mediate parasympathetic signaling in the heart, the autoantibodies against M2-muscarinic receptors (anti-M2-R) were naturally presumed to contribute to AF development. In a cohort of 104 patients with dilated cardiomyopathy, age-matched with 104 patients with idiopathic AF and 104 healthy controls, Baba et al. [8] found that patients with idiopathic AF had a markedly higher prevalence of anti-M2-R as compared to controls. Meanwhile, patients with dilated cardiomyopathy who had
⁎ Corresponding author at: Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan 430060, PR China. E-mail address: [email protected] (H. Jiang).
http://dx.doi.org/10.1016/j.ijcard.2015.06.066 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
documented AF had greater anti-M2-R level than patients who did not have AF. Similar results were also found by Yalcin et al. [9] in patients with lone paroxysmal AF in a recent study in which lone paroxysmal AF patients had significantly higher serum anti-M2-R level than healthy controls and the anti-M2-R level was an independent predictor for the presence of lone paroxysmal AF. In addition, pre-procedural anti-M2-R level was found to predict the recurrence of AF after catheter ablation. Zou et al. [10] reported 76 AF patients with preserved left ventricular systolic function who underwent radiofrequency catheter ablation. They showed that the frequency and titer of serum anti-M2-R in AF patients were significantly higher than those in the control group with sinus rhythm. The multivariate analysis showed that pre-procedural serum anti-M2-R was an independent predictor for the recurrence of AF at the time point of 12 months after ablation (odds ratio: 4.701; 95% confidence interval: 1.590–13.894; p = 0.005). Similar results were also found in paroxysmal AF patients who underwent cryoballoon-based pulmonary vein isolation [11], in which anti-M2-R levels of N277.65 ng/mL was an independent predictor of late AF recurrence. Furthermore, serum anti-M2-R levels were found to predict left atrial fibrosis severity in paroxysmal lone AF patients undergoing cryoablation [12], which may be helpful for selecting appropriate patients for ablation. To investigate the effect of anti-M2-R on atrial electrophysiology, Baba et al. [8] added patients' purified anti-M2-R to chick embryo and demonstrated that purified IgG from AF patients exhibited negative chronotropic effects and induced supraventricular arrhythmias. By using a rabbit model immunized with synthetic peptide corresponding to the M2 muscarinic receptor, Hong et al. [6] demonstrated that anti-M2-R positive rabbits showed a significantly shorter atrial effective refractory period and a longer intra-atrial activation time than control rabbits. M2-immunized rabbits also showed upregulated protein levels of M2 receptor and GIRK4 and upregulated mRNA levels of GIRK1 and GIRK4 (2 homologous genes of KACh). Histological examination revealed significantly increased diffuse fibrotic deposition in anti-M2-R positive rabbit atria compared with control rabbits. These results indicated that anti-M2-R may create arrhythmogenic substrate and participate in the initiation and perpetuation of AF. Besides anti-M2-R, the autoantibodies against the β adrenergic receptors (anti-β-R) were also implicated in promoting the development of AF. In patients with hyperthyroidism, the patients with AF were more likely to have anti-β1-R, as compared to patients without AF [13]. The mean anti-β-R activity was also significantly higher in patients with
Letter to the Editor
AF than those with sinus rhythm [14]. In patients with lone paroxysmal AF, serum anti-β1-R level was significantly higher than healthy controls and the anti-β1-R level was an independent predictor for the presence of lone paroxysmal AF [9]. Just as serum anti-M2-R level plays a predictive role in AF recurrence after catheter ablation, pre-procedural serum anti-β1-R level was also an independent predictor of late AF recurrence following cryoablation in paroxysmal AF patients [11]. In isolated canine pulmonary veins, Stavrakis et al. [13] showed that IgG from anti-β1-R positive patients induced hyperpolarization, decreased action potential duration, enhanced early after depolarizations and facilitated triggered activity. Additionally, anti-β2-R was found to promote atrial arrhythmia vulnerability in a recent study by Li et al. [15]. In 5 rabbits pre- and postimmunization for anti-β2-R, burst atrial pacing was performed before and after the infusion of acetylcholine in incremental concentrations to induce atrial arrhythmias. The results showed that rabbits postimmunization had significantly more episodes of atrial arrhythmias (including AF) when compared to that of preimmunization. Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of β-2 adrenergic receptor in transfected cells in vitro compared to the preimmune sera. Although the cumulative and emerging evidence reveals that the activation of autoantibodies targeting M2-muscarinic and β adrenergic receptors may be contributory or even causal to AF pathogenesis, whether these autoantibodies promote AF, or they are just AF biomarkers or bystanders has always been the focus of controversy [16–19]. Even though experimental studies have demonstrated that the anti-M2-R or anti-β-R was able to induce atrial structural remodeling and electrophysiological remodeling, the underlying molecular mechanisms are still unclear. Meanwhile, the pathophysiology of AF in human is more complex than that in animal models as AF has heterogeneous phenotypes and often coexists in many other diseases. It is probable that these antibodies are both biomarkers and pathophysiological mediators. Further studies are warranted to clarify these issues. Nevertheless, current available researches did offer us a novel etiologic and mechanistic insight into AF. If the causal relationship between anti-M2-R or anti-β-R and AF was confirmed and the detailed mechanisms were illuminated by further clinical and experimental studies, strategies targeting the corresponding pathogenic autoantibodies may be a promising alternative intervention in AF treatment. Conflicts of interest None. Acknowledgment This work was supported by grants 81300181 (BH), 81370281 (ZL) and 81400254 (WH) from the National Natural Science Foundation of China.
181
References [1] A. Kourliouros, I. Savelieva, A. Kiotsekoglou, M. Jahangiri, J. Camm, Current concepts in the pathogenesis of atrial fibrillation, Am. Heart J. 157 (2009) 243–252. [2] U. Schotten, S. Verheule, P. Kirchhof, A. Goette, Pathophysiological mechanisms of atrial fibrillation: a translational appraisal, Physiol. Rev. 91 (2011) 265–325. [3] Z. Lu, B.J. Scherlag, J. Lin, L. Yu, J.H. Guo, G. Niu, et al., Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi, Cardiovasc. Res. 84 (2009) 245–252. [4] Z. Lu, B.J. Scherlag, J. Lin, G. Niu, K.M. Fung, L. Zhao, et al., Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing, Circ. Arrhythm. Electrophysiol. 1 (2008) 184–192. [5] L. Yu, B.J. Scherlag, Y. Sha, S. Li, T. Sharma, H. Nakagawa, et al., Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle, Heart Rhythm. 9 (2012) 804–809. [6] C.M. Hong, Q.S. Zheng, X.T. Liu, F.J. Shang, H.T. Wang, W.R. Jiang, Effects of autoantibodies against M2 muscarinic acetylcholine receptors on rabbit atria in vivo, Cardiology 112 (2009) 180–187. [7] H.C. Lee, K.T. Huang, X.L. Wang, W.K. Shen, Autoantibodies and cardiac arrhythmias, Heart Rhythm. 8 (2011) 1788–1795. [8] A. Baba, T. Yoshikawa, Y. Fukuda, T. Sugiyama, M. Shimada, M. Akaishi, et al., Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy, Eur. Heart J. 25 (2004) 1108–1115. [9] M.U. Yalcin, K.M. Gurses, D. Kocyigit, S.A. Kesikli, A.H. Ates, B. Evranos, et al., Elevated M2-muscarinic and β1-adrenergic receptor autoantibody levels are associated with paroxysmal atrial fibrillation, Clin. Res. Cardiol. 104 (2015) 226–233. [10] C. Zou, Z. Zhang, W. Zhao, G. Li, G. Ma, X. Yang, et al., Predictive value of preprocedural autoantibodies against M2-muscarinic acetylcholine receptor for recurrence of atrial fibrillation one year after radiofrequency catheter ablation, J. Transl. Med. 11 (2013) 7. [11] M.U. Yalcin, K.M. Gurses, D. Kocyigit, S.A. Kesikli, M. Dural, B. Evranos, et al., Cardiac autoantibody levels predict recurrence following cryoballoon-based pulmonary vein isolation in paroxysmal atrial fibrillation patients, J. Cardiovasc. Electrophysiol. (2015), http://dx.doi.org/10.1111/jce.12665. [12] K.M. Gurses, M.U. Yalcin, D. Kocyigit, S.A. Kesikli, U. Canpolat, H. Yorgun, et al., M2-muscarinic acetylcholine receptor autoantibody levels predict left atrial fibrosis severity in paroxysmal lone atrial fibrillation patients undergoing cryoablation, Europace 17 (2015) 239–246. [13] S. Stavrakis, X. Yu, E. Patterson, S. Huang, S.R. Hamlett, L. Chalmers, et al., Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism, J. Am. Coll. Cardiol. 54 (2009) 1309–1316. [14] A. Galloway, H. Li, M. Vanderlinde-Wood, M. Khan, A. Benbrook, C. Liles, et al., Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism, Endocrine (2014), http://dx.doi.org/10.1007/s12020-014-0495-4. [15] H. Li, B.J. Scherlag, D.C. Kem, C. Zillner, S. Male, S. Thirunavukkarasu, et al., Atrial tachycardia provoked in the presence of activating autoantibodies to β2adrenergic receptor in the rabbit, Heart Rhythm. 10 (2013) 436–441. [16] L.J. Field, Lone atrial fibrillation and autoantibodies: cause versus effect, J. Cardiovasc. Electrophysiol. 9 (1998) 618–619. [17] D. Dobrev, T. Christ, U. Ravens, Muscarinic subtype-2 receptor autoantibodies: actors or bystanders in human atrial fibrillation? Eur. Heart J. 25 (2004) 1091–1092. [18] A. Baba, M. Fu, Autoantibodies in atrial fibrillation: actor, biomaker or bystander? Autoimmunity 41 (2008) 470–472. [19] M. Fu, Autoantibodies in atrial fibrillation: actors, biomarkers or bystanders? How far have we come? Cardiology 112 (2009) 178–179.