Muscarinic subtype-2 receptor autoantibodies: actors or bystanders in human atrial fibrillation?

Dobromir Dobrev*, Torsten Christ and Ursula Ravens

Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany

* Correspondence to: Dobromir Dobrev, Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscher Str 74, 01307 Dresden, Germany. Tel.: +49-351-458-6279; fax: +49-351-458-6315
E-mail address: dobrev{at}rcs.urz.tu-dresden.de

This editorial refers to "Autoantibodies against M2 muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy"1 by A. Baba et al. on page 1108

Atrial fibrillation (AF) is currently the most common cardiac arrhythmia in the clinical setting. It is associated with a shortening of action potential duration (APD) and effective refractory period (ERP) and a loss of physiological rate-dependent adaptation that can be explained by concomitant alterations in ion channel activity.1 These electrophysiological changes (electrical remodelling) promote the induction and the persistence of the arrhythmia. In addition, changes in the autonomic nervous system are important for initiation and perpetuation of AF. Vagal stimulation shortens atrial APD and ERP and increases dispersion of atrial ERPs.2 This creates an arrhythmogenic substrate for re-entry of the excitation wave front which may allow the arrhythmia to became sustained. Although there is no doubt that the parasympathetic nervous system contributes to initiation of AF, its precise role in the chronic state of the arrhythmia is currently unknown.

Vagally released acetylcholine (ACh) stimulates muscarinic receptors (M-receptors) and activates the atrial ACh-regulated potassium current (IK,ACh). The subsequent shortening of APD and ERP is mediated by IK,ACh, because in knock-out mice lacking this channel, M-receptor stimulation did not induce AF.3 Thus, if IK,ACh is involved in the initiation and/or perpetuation of AF, its activity should be higher in AF than in SR. Studies in atrial myocytes from patients with chronic AF revealed, however, that both expression of the channel subunits and activation of IK,ACh in response to M-receptor stimulation were lower in AF than in sinus rhythm (SR).4,5 This led to the conclusion that human atrial myocytes probably adapt to the high beating rate by down-regulating IK,ACh to counteract the shortening of APD.4

At first glance, reduced channel expression and limited receptor stimulation of IK,ACh is an unexpected finding. However, AF may be accompanied by spontaneous activity of the M-receptor-mediated signal transduction even in the absence of abnormal vagal activity. Theoretically each component of the signal transduction may become constitutively active during the diseased state. Indeed, the limited M-receptor-mediated stimulation of IK,ACh during human chronic AF is associated with constitutively active IK,ACh channels.6 On the other hand, increasing evidence suggests that activation of G-protein-coupled receptors by autoantibodies may contribute to the pathophysiology of cardiac diseases7–9 and stimulatory M2-receptor autoantibodies (M2-AABs) were detected in sera from patients with dilated cardiomyopathy (DCM).8,9 Since heart failure is one of the most common clinical settings for chronic AF it is reasonable to hypothesise that M2-AABs may participate in the induction and perpetuation of AF in patients with cardiomyopathy.

In this issue, Baba et al.10 investigated whether the presence of M2-AABs is associated with higher prevalence of AF in patients with DCM. Healthy gender- and age-matched subjects, and patients with chronic AF without ventricular dysfunction were used as controls. They found that M2-AABs were present more frequently in patients with DCM (40%) than in healthy subjects and patients with chronic AF (8% and 24%, respectively). In patients with DCM, AF was more common in M2-AAB-positive (40%) than in M2-AAB-negative patients (18%). Besides advanced age and enhanced plasma levels of atrial natriuretic peptide, the presence of M2-AABs was the strongest independent predictor for development of AF in patients with DCM. This suggests that M2-AABs change atrial electrophysiology in a way which promotes the perpetuation of AF in these patients. In chick embryos, M2-AAB-positive sera from patients with chronic AF or DCM produced negative chronotropic effects and induced atrial arrhythmias suggesting that M2-AABs may promote the development of chronic AF in patients with and without DCM. How do these findings improve our understanding of the molecular mechanisms of chronic AF?

The major contribution of this study is to provide new evidence for the potential role of the M-receptor-mediated signal transduction in human chronic AF. It extends previous results showing that the limited M-receptor-mediated stimulation of IK,ACh during human chronic AF is associated with constitutively active IK,ACh channels.6 The presence of circulating M2-AABs may exert a tonic activation of M-receptor signal transduction and is expected to strengthen the effect of constitutively active IK,ACh on heterogeneity of ERP. The chronically increased dispersion of atrial ERP will create an arrhythmogenic substrate for the perpetuation of AF. On the other hand, the ACh concentrations in the synaptic clefts could be elevated because of reduced activity of its degrading enzyme acetylcholine esterase.11 At present it is unclear whether elevated synaptic ACh concentrations and presence of M2-AABs reinforce each other or may interfere due do receptor down-regulation. In contrast to M-receptor agonists, M2-AABs were shown not to desensitize the M2-receptors.12 Further studies are needed to clarify these issues.

The study of Baba et al.10 also suggests that atrial electrical remodelling in M2-AAB-positive AF patients with DCM may differ from M2-AAB-negative patients. In patients with advanced heart failure subsequent development of AF is associated with higher mortality than in DCM patients without AF.13 AF patients with reduced left ventricular function benefit from treatment with ACE-inhibitors.14 Whether this holds true for M2-AAB-positive patients is currently unknown and warrants further clinical studies. In conclusion, the study of Baba et al.10 contributes to our understanding of the role of the parasympathetic nervous system to pathophysiology of chronic AF. The present study does not answer the question of whether M2-AABs are the cause of AF or simply by-standers in the clinical settings. Based on the growing evidence for involvement of autoimmune mechanisms in cardiovascular diseases there is a clear need for development of suitable therapeutic strategies. Thus, removal of M2-AABs via immunoadsorption for example may represent a new therapeutic option for AF patients positive for M2-AABs.

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (DO 769/1), by the German Atrial Fibrillation Network (AFNET) and the MeDDrive-Programme (Medical Faculty, Dresden University of Technology).

Footnotes

1 10.1016/j.ehj.2004.05.012 Back

References

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