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Cardiovascular Research Advance Access originally published online on June 17, 2009
Cardiovascular Research 2009 84(1):15-23; doi:10.1093/cvr/cvp203
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

The role of connexin40 in atrial fibrillation

Sevasti-Maria Chaldoupi1, Peter Loh1, Richard N.W. Hauer1, Jacques M.T. de Bakker1,2,3 and Harold V.M. van Rijen4,*

1 Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, The Netherlands
2 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
3 Heart Failure Center, Academic Medical Center University of Amsterdam, The Netherlands
4 Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Alexander Numan Building, Yalelaan 50, 3584 CM Utrecht, The Netherlands

* Corresponding author. Tel: +31 30 253900; fax: +31 30 2539036. E-mail address: h.v.m.vanrijen{at}umcutrecht.nl

Received 21 January 2009; revised 3 June 2009; accepted 14 June 2009

Time for primary review: 21 days


   Abstract
Top
 Abstract
1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
 References
 
Connexin40 (Cx40) is a major gap-junction protein in the atrial myocardium. In the heart, gap junctions are responsible for cell-to-cell conduction of the action potential. In several cardiac diseases, the expression of connexins is changed and is associated with increased propensity for arrhythmias. Atrial fibrillation (AF) is the most common arrhythmia in man with a diverse clinical presentation, different underlying mechanisms, and difficult treatment. The vulnerability to arrhythmias of the heart is determined by the combined presence of an arrhythmogenic substrate and initiating triggers. The arrhythmogenic substrate is formed by reduced effective refractory period, enhanced spatial dispersion of refractoriness, or abnormal atrial impulse conduction. Initiating triggers of AF most frequently originate from firing foci in the pulmonary veins and/or superior caval vein. Prolonged episodes of AF result in electrical and structural remodelling that favours the reoccurrence or perpetuation of AF. This electrical remodelling embodies changes in Cx40 expression and distribution, both in the atrial myocardium itself and in the thoracic veins. In addition, Cx40 gene mutations or polymorphisms give an inherited predisposition to AF. This review focuses on the role of Cx40 in AF, showing that abnormal Cx40 expression is correlated with both trigger formation from the thoracic veins as well as enhanced vulnerability of the atrial myocardium to AF.

KEYWORDS Connexins; Atrial fibrillation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
 References
 
Atrial fibrillation (AF) is the most commonly encountered sustained arrhythmia in man with a variable clinical presentation.1 Besides AF secondary to hypertension, coronary artery diseases, valvular abnormalities, cardiothoracic surgery, cardiomyopathy, inflammatory or infiltrative processes, endocrine disorders, and drug abuse, idiopathic AF is observed in 30% or more of patients.1 In addition, Cx40 gene mutations or polymorphisms give an inherited predisposition to AF.

In general, the vulnerability to arrhythmias of the heart is determined by the combined presence of an arrhythmogenic substrate and initiating triggers, both of which can be modulated by the autonomic nervous system or drugs.2 In patients prone to AF, the triggered activity originates mainly from the thoracic veins.3 These triggers combined with an atrial arrhythmogenic electrophysiologic substrate, caused by reduced effective refractory period (ERP),4–7 enhanced spatial dispersion of refractoriness8 or abnormal atrial impulse conduction9,10 lead to the initiation of AF.

AF is a self-perpetuating progressive disease in which ‘AF begets AF’.6 Prolonged episodes of AF result in electrical and structural remodelling that favours the reoccurrence or perpetuation of AF. Fast atrial rhythms and AF give rise to electrical remodelling, i.e. changes in ion-, and gap-junction channel expression.4–7 Structural remodelling, detected at a later stage, involves changes in mitochondrial size and the disruption of sarcoplasmic reticulum at the subcellular level, myocardial cell hypertrophy at the cellular level, and fibre disarray and increased collagen deposition at the tissue level.5

Electrical remodelling associated with AF lead to changes in the ERP.4–7 As part of this electrical remodelling, changes in gap junctions and connexins in AF have been reported,11–14 but this do not fall into a consistent pattern. Gap junctions are clusters of transmembrane channels that link adjoining cells and mediate cell-to-cell electrical coupling and communication. They are formed by the joining of two connexons (=hexameric hemi-channels), which are composed of six integral membrane subunits, connexins (Cx), that surround the central aqueous pore.15 In the human heart, four main isoforms are expressed.16 Cx43 is expressed in all chambers of the heart, but predominantly in the ventricles, Cx45 is found in the conduction system of the heart and at low levels in the atrial and ventricular working myocardium,17 and Cx37 is located in the endothelial gap junctions in many vessels. Finally, Cx40 is expressed mainly in the atrial working myocardium, the conduction system, and the vasculature. Cx40 was first described in a range of animal species,18,19 and subsequently mapped to human chromosome 1. It became apparent that Cx40 was expressed in the atrioventricular conduction system20,21 and abundantly expressed in the atrial but not in the ventricular gap junctions.22,23 Recently, a new connexin was described in the mouse heart, i.e. Cx30.2 (the human equivalent is Cx31.9) which in mice seems responsible for slowing of impulse conduction in the atrioventricular node.24 However, the role of Cx31.9 in the human heart is unclear, for it is not detectable in the human cardiac conduction system.25

Several reviews described the mechanisms of AF26–29 or changes in Cx expression in cardiac disease.30,31 This review focuses on the role of Cx40 in AF, showing that the abnormal Cx40 expression is correlated to both trigger formation from the thoracic veins as well as enhanced vulnerability of the atrial myocardium to AF.


   2. Contribution of Cx40 to the atrial electrical propagation
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
 References
 
Cell-to-cell coupling by gap junctions is an essential determinant in uniform and successful propagation of the action potential and determined by the distribution and specific properties of connexins throughout the myocardium.32 In the human atria, Cx40 and Cx43 are the major connexins,16 and several experimental studies attempted to elucidate their role in myocardial conduction. Studies in Cx43 haploinsufficient mice have shown that P-wave duration is not affected by Cx43 levels, suggesting unchanged conduction velocity (CV) in the atria.33 Even levels of only 10% Cx43 did not significantly increase P-wave duration in the atria of mice.34 These studies indicated that Cx43 is not a principal determinant for atrial impulse conduction in the presence of normal Cx40 levels.

Several studies in Cx40 knockout mice (Cx40–/–) indicated that Cx40 is the dominant connexin for impulse conduction in the atria and the conduction system as summarized in Table 1. The majority of these studies demonstrated that full deficiency for Cx40 prolonged P-wave, PQ/PR interval, QRS, and QTc duration in the surface electrocardiogram.35–42 Epicardial mapping revealed that the prolonged P-wave and PQ/PR-interval were due to reduced CV in the atria, while the prolonged QRS complex was caused by right bundle branch block and reduced CV in the left bundle branch.42,43 Typically, Cx40 knockout mice were susceptible to atrial tachyarrhythmias.35–38,42


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  		Table 1 Studies on Cx40 knockout mice

 
Although in mice, all studies are unambiguous, in respect to electrical propagation, Beauchamp et al.44 showed in synthetic strands of neonatal and foetal murine atrial cardiomyocytes that Cx40 deletion (Cx40–/–) was associated with increased electrical propagation velocity and genetic deletion of Cx43 (Cx43–/–) produced a decrease in propagation velocity. In addition, a study that investigated the correlation between Cx40 and Cx43 expression in the atria and the atrial conduction properties in humans showed that the propagation velocity in the atria is related to the interactions between Cx40 and Cx43 expression.45 A higher expression of immunodetectable Cx40 in the right atrium, in the presence of Cx43, reduced CV, while Cx43 alone was not directly correlated with propagation properties. The ratio of Cx43 to total Cx immunosignal (Cx43/[Cx40 + Cx43]) was directly and the ratio of Cx40 to total Cx (Cx40/[Cx40 + Cx43]) was inversely related to propagation velocity. These findings may be explained by the fact that heterotypic Cx40/Cx43 gap-junction channels may be present, which have much lower conductance than either Cx40 or Cx43 homotypic gap-junction channels.46,47 These data, however, are in contrast with the previously discussed mouse data, in which haploinsufficiency for Cx40 did not alter atrial impulse conduction and full deficiency for Cx40 is associated with lower impulse conduction. The apparent discrepancy between Cx40–/– mouse data and the latter in vitro and human data may be explained by specific expression patterns in adult mouse myocytes,44 and the fact that in transgenic animals altered expression of genes other than those targeted may occur.


   3. Role of Cx40 distribution in maintenance of atrial fibrillation
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
 References
 
The first studies to investigate the role of gap junctions in AF were carried out in animal models of AF (Table 2). Induction of persistent AF (lasting >2 months) in a goat model was reported to lead to heterogeneous spatial distribution of Cx40, while the expression of Cx43 remained unchanged.12 Heterogeneous expression was defined as the non-uniform labelling pattern of Cx40: patches of cells virtually devoid of Cx40, next to areas with almost normal expression of Cx4012. This heterogeneous distribution occurred after 2 weeks of high-rate atrial pacing.48 Interestingly, discontinuation of AF resulted in reverse remodelling and gradual normalization of the altered distribution pattern of gap junctions and Cx40 expression.49 Total Cx40 protein levels were unchanged or reduced in long lasting AF with unchanged levels of Cx40 mRNA.12,48,50


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  		Table 2 Cx40 expression and distribution in atrial myocardium during atrial fibrillation

 
In humans, several studies investigated connexin expression and distribution during AF (Table 2) under different conditions. During sinus rhythm (SR), gap junctions are expressed mainly at the true end of the cells,51–54 although side-to-side dispositions can also be common in the atria.54 During AF, however, Cx40 expression was predominantly side-to-side51,53,54 and heterogeneously distributed,11,53,55–57 while the expression of N-cadherin and Desmoplakin remained normal.53 In patients, with ischaemic heart disease and no history of arrhythmias, post-operative AF was more likely when pre-existing higher levels of Cx40 protein were present.52 Other studies, however, that investigated changes in Cx40 expression and distribution in patients with long-lasting AF (at least 3 months and thus atrial remodelling) showed inconsistent results with respect to the amount of Cx40 protein level during AF. Some of those studies showed that the Cx40 protein levels were increased with lateralized expression in the atria, independent of AF aetiology.54,58 Other studies found that the expression of Cx40 during AF was significantly reduced,11,53,55,59 whereas various studies showed no difference in Cx40 protein expression levels between patients with SR and long lasting AF11,56,57 or that Cx40 expression levels were dependent on extracellular Ca++ level.51

These seemingly different findings from the studies to date may in part be due to the different methodological approaches and experimental design. First, both polyclonal rabbit anti-rat Cx40 (S15) and anti-human Cx40 specific antibodies (Y2IY) were used in different studies for the quantification of Cx40. The affinity of both antibodies to Cx40, however, was shown to be comparable.60 Secondly, the different methods of western blot or immunofluorescent confocal analysis, which were used for Cx40 analysis, both have restrictions and limitations for the interpretation of the amount of Cx40 (reviewed in ref. 29). Finally, the use of small, non-representative atrial tissue for connexin analysis and the inclusion of patients with different pathophysiological causes of AF may play an additional role in the conflicting results.

However, almost all studies pointed out that Cx40 gap junctions are heterogeneously distributed in the atria of patients with AF (Table 2). Such an expression of connexins may result in heterogeneous intercellular coupling leading to conduction defects and non-uniform anisotropic characteristics that can facilitate re-entrant circuits and therefore predispose to atrial tachycardias.61 A second effect of inhomogeneous uncoupling might be the increased dispersion in refractoriness. Uncoupling was shown to lead to a dramatic increase in activation recovery intervals.62

Interestingly, in heart failure, the heterogeneous expression of Cx43 is associated with both dispersion of impulse conduction63,64 and dispersion of refractoriness.63


   4. The role of Cx40 in the arrhythmogenic properties of the thoracic veins in atrial fibrillation
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
 References
 
Triggers emerging from the thoracic veins, i.e. the pulmonary veins (PVs)3 and the superior vena cava (SVC),65 are important factors in the initiation and perpetuation of AF.3,65 So called myocardial sleeves, the extensions of atrial myocardium into the PVs and SVC, are well described66 and identified as the underlying substrate for these triggers. The mechanisms behind the ectopic activity from the thoracic veins are thought to be based on either automaticity or micro-re-entry and the possible role of Cx40 in this arrhythmogenic behaviour has been subject of several studies (Table 3).


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  		Table 3 Cx40 expression and distribution in the thoracic veins

 
Ectopic activity from the PVs is the most prominent triggers for AF.3 Saito et al.67 studied the anatomy of the PVs in human hearts and showed that the myocardial cells in the PVs are separated from the muscular media of the veins suggesting that the trigger from the PVs must originate from the myocardial sleeves. Arora et al.68 showed that the conduction at the proximal part of canine PVs was considerably slower than in the remaining left atrium (LA). Also in canine PVs, Hocini et al.69 found zones of activation delay that were related to sudden changes in fibre direction that could result in micro-re-entry and suggested that Cx distribution and expression might play a supplementary role. Evidence for this was provided by Verheule et al.13 who demonstrated that, although the myocytes in the canine PVs were similar to those in LA, the gap junctions in the myocardial sleeves expressed mainly Cx43 and that the levels of Cx40 were significantly lower than in the LA. On the other hand, spontaneous electrical activity was observed in PVs isolated from guinea pig hearts.70 The response of this spontaneous activity to perivascular nerve stimulation was similar to that seen at sinoatrial node (SAN).70 Node-like cells were identified in myocardial sleeves of PVs of adult rats and the intercalated disk of those cells were composed of small gap-junctional specializations comparable to those seen in the SAN.71,72 Furthermore, these myocardial sleeves correspond to areas of the conduction system in embryonic myocardium and originate from the sinus venosus segment of the heart from which also the SAN originates.73,74 Cells of the PV sleeves originate from mesenchymal stem cells and are not recruited from atrial cells.75

Studies in dogs with atrial remodelling due to mitral valve regurgitation or rapid atrial pacing demonstrated that Cx40 protein expression in the PVs was downregulated which may be important for the maintenance of AF.76,77 In summary, in PVs, both automaticity and activation delay resulting in micro-re-entry may form the source of triggers for AF. Gap-junction remodelling seems to play an important role in two ways. First, the fact that the PVs contain autorhythmic cells, which share a sinus nodal-like gap-junction expression, may be able to drive the atria. Secondly, abnormal and discontinuous gap-junction expression with rapid changes in fibre direction may facilitate micro-re-entry, resulting in pre-excitatory triggering of the atrial myocardium.

In the SVC, myocardial sleeves also extend from the RA-SVC junction up to 2–5 cm into the SVC.78,79 Yeh et al.80 studied the electrical properties of the SVC in canine hearts that are structurally comparable to human SVC. In SVC myocardial sleeves, gap junctions composed of Cx40, Cx43, and Cx45 were exclusively found at the intercalated disk. The distribution of Cx40 was homogeneous throughout the myocardial sleeves. In the proximal part of the sleeves, atypical areas were present that extended to 1 cm distally from the RA-SVC junction where Cx43 expressed in the centre, surrounded by Cx40 spots. Interestingly, the Cx expression pattern of these atypical areas is analogous to that reported for SAN of dogs.81 Automaticity of SVC cells was evidenced by the findings of Chen et al.,82 who studied the electrical properties of the myocardial sleeves in the SVC. The SAN-like Cx expression pattern may favour the exit of activity from spontaneously active cells to surrounding myocardium. The investigators not only demonstrated pacemaker activity of some of the cardiomyocytes in the SVC, but also showed the presence of delayed after depolarization in a large percentage of cells suggesting that the triggered activity plays an additional role in the ectopic activity in SVC.

In a dog model of rapid atrial pacing, pacing for 2 and 6–8 weeks resulted in electrical and structural remodelling of the myocardial sleeves in SVC.14 Beside changes in size, arrangement, and proliferation of myocytes, there was perceptible remodelling of the gap-junction distribution and Cx expression. During the first 2 weeks of continuous pacing, an upregulation of Cx43 and a downregulation of Cx40 occurred and Cx were redistributed to the lateral borders of individual cardiomyocytes. Rapid pacing also resulted in shortening of the refractory period, decreased CV of the myocardial sleeves, and increased vulnerability to AF.83 Alterations in cell-to-cell coupling may contribute to this observed change in velocity.84

The specific pattern of Cx expression, combined with the intrinsic automaticity of SVC myocytes may determine the mechanism for triggers emerging from the SVC69 under normal conditions. During AF, however, the alteration in the expression and distribution of Cx40 may change the electrical characteristics of the SVC and cause inhomogeneous and discontinuous propagation of the impulse as well as activation delay through the myocardial sleeves, a substrate supporting re-entry.


   5. The Cx40 gene mutations and polymorphisms and atrial fibrillation predisposition
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
6. Factors modulating Cx40
 7. Conclusion
 References
 
AF has a variable clinical presentation and character, which may result from a genetic substrate with different gene mutations and/or polymorphisms. Familial forms of AF, due to gene mutations or polymorphisms, have been described. An autosomal dominant trait of AF was first described in a small family in Spain by Brugada et al.85 Loss- or gain-of-function mutations in several potassium (K+) channel genes (KCNQ1, KCNE2, KCNJ2, and KCNA5) have been described in familial forms of AF.86–89 Furthermore, relatives of probands with lone AF are at substantially increased risk of developing this arrhythmia as well, suggesting a hereditary origin.90–94 Besides gene mutations, many gene polymorphisms are described in idiopathic AF, such as polymorphisms of angiotensin converting enzyme,95 potassium channels gene polymorphisms,96 and sodium channels gene polymorphisms.97

Besides ion channels, abnormalities in the Cx40 gene (GJA5) have been reported to be associated with atrial arrhythmias. Groenewegen et al.98 were the first to connect the Cx40 gene with a rare atrial arrhythmia in humans. They showed that atrial standstill, a disease characterized by lack of electrical and mechanical activity of the atria, was due to a combination of a rare polymorphism of the promoter of the Cx40 gene at nucleotides, –44 (G->A) and +71 (A->G), that occurs in 7% in the population, with a novel mutation in the sodium channel gene SCN5A. They demonstrated that patients with either the SCN5A mutation or the presence of that Cx40 polymorphism did not show evidence of atrial standstill. Only the combined effect of those genetic variants led to an additive and progressive pathological response and the presence of atrial standstill.

Firouzi et al.99 were the first to correlate the vulnerability for AF to this Cx40 promotor polymorphism in patients without structural heart disease in the absence of atrial remodelling. They compared the electrophysiologic characteristics of 30 patients with supraventricular tachycardia and very rare episodes of AF with those without evidence of AF or history of episodes with irregular heartbeat. They illustrated that homozygous carriers of the minor haplotype (–44AA/+71GG) were more prone to both inducibility of AF by programmed electrical stimulation and spontaneous occurrence of AF episodes. This predisposition to initiation of AF appeared to be related to enhanced dispersion of atrial refractoriness. Juang et al.100 showed the same relation in Taiwanese patients with paroxysmal or permanent AF. They showed that patients with AF (n = 173) had a significant higher Cx40 (–44AA/+71GG) genotype frequency compared with the control group (232 patients). Finally, Gollob et al.101 studied 15 patients with idiopathic AF with early onset (±45 years) and refractory to pharmacological therapy. They identified four novel, three somatic, and one germline, heterozygous mutations in the Cx40 gene in four of those patients.

Functional studies in cell lines have shown that the promoter activity of Cx40 with the minor allele (–44A/+71G) was significantly reduced compared with the major allele (–44G/+71A).98,100 To what extend the levels or distribution of Cx40 protein is decreased due to this polymorphism is unclear yet. Further studies are needed to correlate the presence of the minor allele (–44A/+71G) to changes in the Cx40 protein level. Atrial sample of patients with mutations in the Cx40 gene showed abnormal gap-junction formation with intracellular accumulation of Cx40.101 This abnormal expression and distribution of Cx40 protein presumably leads to heterogeneous impulse propagation that may increase AF vulnerability.


   6. Factors modulating Cx40
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
7. Conclusion
 References
 
Since abnormal expression of Cx40 is closely related to the vulnerability to AF, normalization of Cx40 expression may be a successful therapeutic avenue. However, little is known about the mechanisms that underlie atrial remodelling in general (e.g. reviewed by Brundel et al.102) and factors that specifically modulate Cx40 function during AF. Recently, Sarrazin et al.103 showed that oral administration of n-3 polyunsaturated fatty acids can result in reduced vulnerability to induction of AF in dogs.64 This protection against AF was mostly related to reduced Cx40 expression levels. Agents that modify the phosphorylation state of connexins would be a potential pathway for regulating cell-to-cell coupling during AF. For Cx43, it is known that dephosphorylation is associated with intercellular redistribution and electrical uncoupling.104–107 Only one study has directly shown the improvement of electrical coupling through Cx40-based gap junctions by cAMP-mediated phosporylation.108 Whether this also occurs in vivo is unclear at current.

A potential new antiarrhythmic agent, the so-called antiarrhythmic peptides (AAPs) have been described to improve gap-junctional conductance with antiarrhythmic potential.109 They were mainly studied to explore their antiarrhythmic character in the ventricular myocardium which resulted in reduced dispersion of action potential duration110–112 and enhancement of gap-junctional conductance.113–117 The effect of rotigaptide (also known as ZP123, a potent AAP analog with improved plasma stability) on AF was subject of several studies. In a rabbit model of volume overload-induced AF, rotigaptide increased atrial CV, however, without the reduction of AF vulnerability.118 The expression levels of Cx43 and Cx40 were down regulated in the model, but remained unaltered after rotigaptide treatment. Similarly, in a dog model of AF resulting from either atrial or ventricular tachy-pacing, rotigaptide improved CV, without altering AF duration or vulnerability.119 However, in a dog model of AF due to myocardial ischaemia, the addition of rotigaptide prevented ischaemia-induced conduction slowing and reduced AF duration. Similar results were obtained in a canine sterile pericarditis model, in which GAP-134 (like rotigaptide an AAP analog) was able to reduce AF.120 Additional studies in rats showed that ZP123 prevents the reduction of atrial CV during metabolic stress;118,121 however, the drug had no effect under normal physiological conditions.121

Many studies have shown that Cx function can be modified.122–124 However, further research is needed to establish which Cx modifier is most successful for the treatment of AF.


   7. Conclusion
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
References
 
In this review, we have focused on the role of Cx40 in the initiation and maintenance of AF. Direct manipulation of the Cx40 amount in mice is related to conduction slowing and vulnerability to AF (in the absence of other structural or electrical remodelling). In patients with AF, Cx40 expression is heterogeneous, which may lead to abnormal impulse formation and conduction, which may form the substrate for AF. Altered Cx40 expression and distribution in the myocardial sleeves of the thoracic veins may be the substrate for abnormal impulse formation and/or micro-re-entry, underlying the trigger for AF initiation. At the same time, a genetic predisposition, due to Cx40 gene polymorphism or other short mutations, seems also to be related to the initiation of AF. One last point of discussion may be the redundancy of connexins in the heart. For Cx43, it has been shown that a 50% reduction in Cx43 does not alter ventricular impulse conduction125,126 and mice haploinsufficient for Cx40 do not have an electrical phenotype. Therefore, changes in Cx40 expression alone may not be sufficient for conduction slowing and arrhythmogenesis. The aetiology of AF is not equal between patients, as a result of which the contribution of Cx40 abnormalities may vary. Other factor, such as enhanced fibrosis, as often found during AF,53,127 may be prerequisite for conduction slowing and enhanced arrhythmogenesis. Finally, therapies involving enhancement of Cx function using anti-arrhythmogenic peptides have been proved successful, underlining the role of Cx40 as potential target for AF therapy.

Conflict of interest: none declared.


   References
Top
 Abstract
 1. Introduction
 2. Contribution of Cx40...
 3. Role of Cx40...
 4. The role of...
 5. The Cx40 gene...
 6. Factors modulating Cx40
 7. Conclusion
 References
 

  1. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J (2006) 27:1979–2030.[Free Full Text]
  2. Coumel P, Zimmermann M, Funck-Brentano C. Exercise test: arrhythmogenic or antiarrhythmic? Rate-dependency vs. adrenergic-dependency of tachyarrhythmias. Eur Heart J (1987) 8(Suppl. D):7–15.[Abstract]
  3. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med (1998) 339:659–666.[Abstract/Free Full Text]
  4. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation (1998) 98:2202–2209.[Abstract/Free Full Text]
  5. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation (1995) 91:1588–1595.[Abstract/Free Full Text]
  6. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation (1995) 92:1954–1968.[Abstract/Free Full Text]
  7. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation (1996) 94:2953–2960.[Abstract/Free Full Text]
  8. Ramanna H, Hauer RN, Wittkampf FH, de Bakker JM, Wever EF, Elvan A, et al. Identification of the substrate of atrial vulnerability in patients with idiopathic atrial fibrillation. Circulation (2000) 101:995–1001.[Abstract/Free Full Text]
  9. Ikeda T, Czer L, Trento A, Hwang C, Ong JJ, Hough D, et al. Induction of meandering functional reentrant wave front in isolated human atrial tissues. Circulation (1997) 96:3013–3020.[Abstract/Free Full Text]
  10. Konings KT, Kirchhof CJ, Smeets JR, Wellens HJ, Penn OC, Allessie MA. High-density mapping of electrically induced atrial fibrillation in humans. Circulation (1994) 89:1665–1680.[Abstract/Free Full Text]
  11. Kanagaratnam P, Cherian A, Stanbridge RD, Glenville B, Severs NJ, Peters NS. Relationship between connexins and atrial activation during human atrial fibrillation. J Cardiovasc Electrophysiol (2004) 15:206–216.[CrossRef][Web of Science][Medline]
  12. van der Velden, van Kempen MJ, Wijffels MC, van ZM, Groenewegen WA, Allessie MA, et al. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol (1998) 9:596–607.[Web of Science][Medline]
  13. Verheule S, Wilson EE, Arora R, Engle SK, Scott LR, Olgin JE. Tissue structure and connexin expression of canine pulmonary veins. Cardiovasc Res (2002) 55:727–738.[Abstract/Free Full Text]
  14. Yeh HI, Lai YJ, Lee SH, Chen ST, Ko YS, Chen SA, et al. Remodeling of myocardial sleeve and gap junctions in canine superior vena cava after rapid pacing. Basic Res Cardiol (2006) 101:269–280.[CrossRef][Web of Science][Medline]
  15. Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC. Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev (2003) 83:1359–1400.[Abstract/Free Full Text]
  16. van Veen AA, van Rijen HV, Opthof T. Cardiac gap junction channels: modulation of expression and channel properties. Cardiovasc Res (2001) 51:217–229.[Abstract/Free Full Text]
  17. Vozzi C, Dupont E, Coppen SR, Yeh HI, Severs NJ. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol (1999) 31:991–1003.[CrossRef][Web of Science][Medline]
  18. Kanter HL, Saffitz JE, Beyer EC. Cardiac myocytes express multiple gap junction proteins. Circ Res (1992) 70:438–444.[Abstract/Free Full Text]
  19. Beyer EC, Reed KE, Westphale EM, Kanter HL, Larson DM. Molecular cloning and expression of rat connexin40, a gap junction protein expressed in vascular smooth muscle. J Membr Biol (1992) 127:69–76.[Web of Science][Medline]
  20. Gourdie RG, Severs NJ, Green CR, Rothery S, Germroth P, Thompson RP. The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci (1993) 105:985–991.[Abstract]
  21. Willecke K, Jungbluth S, Dahl E, Hennemann H, Heynkes R, Grzeschik KH. Six genes of the human connexin gene family coding for gap junctional proteins are assigned to four different human chromosomes. Eur J Cell Biol (1990) 53:275–280.[Web of Science][Medline]
  22. Davis LM, Kanter HL, Beyer EC, Saffitz JE. Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. J Am Coll Cardiol (1994) 24:1124–1132.[Abstract]
  23. Gros D, Jarry-Guichard T, Ten VI, de MA, van Kempen MJ, Davoust J, et al. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. Circ Res (1994) 74:839–851.[Abstract/Free Full Text]
  24. Bukauskas FF, Kreuzberg MM, Rackauskas M, Bukauskiene A, Bennett MV, Verselis VK, et al. Properties of mouse connexin 30.2 and human connexin 31.9 hemichannels: implications for atrioventricular conduction in the heart. Proc Natl Acad Sci USA (2006) 103:9726–9731.[Abstract/Free Full Text]
  25. Kreuzberg MM, Liebermann M, Segschneider S, Dobrowolski R, Dobrzynski H, Kaba R, et al. Human connexin31.9, unlike its orthologous protein connexin30.2 in the mouse, is not detectable in the human cardiac conduction system. J Mol Cell Cardiol (2009) 46:553–559.[CrossRef][Web of Science][Medline]
  26. Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev (2007) 87:425–456.[Abstract/Free Full Text]
  27. Nattel S, Shiroshita-Takeshita A, Brundel BJ, Rivard L. Mechanisms of atrial fibrillation: lessons from animal models. Prog Cardiovasc Dis (2005) 48:9–28.[CrossRef][Web of Science][Medline]
  28. Shimizu A, Centurion OA. Electrophysiological properties of the human atrium in atrial fibrillation. Cardiovasc Res (2002) 54:302–314.[Abstract/Free Full Text]
  29. Duffy HS, Wit AL. Is there a role for remodeled connexins in AF? No simple answers. J Mol Cell Cardiol (2008) 44:4–13.[CrossRef][Web of Science][Medline]
  30. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res (2008) 80:9–19.[Abstract/Free Full Text]
  31. Saffitz JE, Hames KY, Kanno S. Remodeling of gap junctions in ischemic and nonischemic forms of heart disease. J Membr Biol (2007) 218:65–71.[CrossRef][Web of Science][Medline]
  32. Jalife J, Morley GE, Vaidya D. Connexins and impulse propagation in the mouse heart. J Cardiovasc Electrophysiol (1999) 10:1649–1663.[Web of Science][Medline]
  33. Thomas SA, Schuessler RB, Berul CI, Beardslee MA, Beyer EC, Mendelsohn ME, et al. Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction. Circulation (1998) 97:686–691.[Abstract/Free Full Text]
  34. Eckardt D, Theis M, Degen J, Ott T, van Rijen HV, Kirchhoff S, et al. Functional role of connexin43 gap junction channels in adult mouse heart assessed by inducible gene deletion. J Mol Cell Cardiol (2004) 36:101–110.[CrossRef][Web of Science][Medline]
  35. Bagwe S, Berenfeld O, Vaidya D, Morley GE, Jalife J. Altered right atrial excitation and propagation in connexin40 knockout mice. Circulation (2005) 112:2245–2253.[Abstract/Free Full Text]
  36. Bevilacqua LM, Simon AM, Maguire CT, Gehrmann J, Wakimoto H, Paul DL, et al. A targeted disruption in connexin40 leads to distinct atrioventricular conduction defects. J Interv Card Electrophysiol (2000) 4:459–467.[CrossRef][Web of Science][Medline]
  37. Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B, Willecke K. Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. Circulation (1999) 99:1508–1515.[Abstract/Free Full Text]
  38. Kirchhoff S, Nelles E, Hagendorff A, Kruger O, Traub O, Willecke K. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol (1998) 8:299–302.[CrossRef][Web of Science][Medline]
  39. Simon AM, Goodenough DA, Paul DL. Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr Biol (1998) 8:295–298.[CrossRef][Web of Science][Medline]
  40. Tamaddon HS, Vaidya D, Simon AM, Paul DL, Jalife J, Morley GE. High-resolution optical mapping of the right bundle branch in connexin40 knockout mice reveals slow conduction in the specialized conduction system. Circ Res (2000) 87:929–936.[Abstract/Free Full Text]
  41. VanderBrink BA, Sellitto C, Saba S, Link MS, Zhu W, Homoud MK, et al. Connexin40-deficient mice exhibit atrioventricular nodal and infra-Hisian conduction abnormalities. J Cardiovasc Electrophysiol (2000) 11:1270–1276.[CrossRef][Web of Science][Medline]
  42. Verheule S, van Batenburg CA, Coenjaerts FE, Kirchhoff S, Willecke K, Jongsma HJ. Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol (1999) 10:1380–1389.[Web of Science][Medline]
  43. van Rijen HV, van Veen TA, van Kempen MJ, Wilms-Schopman FJ, Potse M, Krueger O, et al. Impaired conduction in the bundle branches of mouse hearts lacking the gap junction protein connexin40. Circulation (2001) 103:1591–1598.[Abstract/Free Full Text]
  44. Beauchamp P, Yamada KA, Baertschi AJ, Green K, Kanter EM, Saffitz JE, et al. Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circ Res (2006) 99:1216–1224.[Abstract/Free Full Text]
  45. Kanagaratnam P, Rothery S, Patel P, Severs NJ, Peters NS. Relative expression of immunolocalized connexins 40 and 43 correlates with human atrial conduction properties. J Am Coll Cardiol (2002) 39:116–123.[Abstract/Free Full Text]
  46. Valiunas V, Gemel J, Brink PR, Beyer EC. Gap junction channels formed by coexpressed connexin40 and connexin43. Am J Physiol Heart Circ Physiol (2001) 281:H1675–H1689.[Abstract/Free Full Text]
  47. Valiunas V, Weingart R, Brink PR. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ Res (2000) 86:E42–E49.[Web of Science][Medline]
  48. van der Velden, Ausma J, Rook MB, Hellemons AJ, van Veen TA, Allessie MA, et al. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res (2000) 46:476–486.[Abstract/Free Full Text]
  49. Ausma J, van der Velden HMW, Lenders MH, van Ankeren EP, Jongsma HJ, Ramaekers FC, et al. Reverse structural and gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circulation (2003) 107:2051–2058.[Abstract/Free Full Text]
  50. Thijssen VL, van der Velden HMW, van Ankeren EP, Ausma J, Allessie MA, Borgers M, et al. Analysis of altered gene expression during sustained atrial fibrillation in the goat. Cardiovasc Res (2002) 54:427–437.[Abstract/Free Full Text]
  51. Dhein S, Duerrschmidt N, Scholl A, Boldt A, Schulte JS, Pfannmuller B, et al. A new role for extracellular Ca2+ in gap-junction remodeling: studies in humans and rats. Naunyn Schmiedebergs Arch Pharmacol (2008) 377:125–138.[CrossRef][Web of Science][Medline]
  52. Dupont E, Ko Y, Rothery S, Coppen SR, Baghai M, Haw M, et al. The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation (2001) 103:842–849.[Abstract/Free Full Text]
  53. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res (2002) 54:361–379.[Abstract/Free Full Text]
  54. Polontchouk L, Haefliger JA, Ebelt B, Schaefer T, Stuhlmann D, Mehlhorn U, et al. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol (2001) 38:883–891.[Abstract/Free Full Text]
  55. Nao T, Ohkusa T, Hisamatsu Y, Inoue N, Matsumoto T, Yamada J, et al. Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol (2003) 91:678–683.[CrossRef][Web of Science][Medline]
  56. Li JY, Lai YJ, Yeh HI, Chen CL, Sun S, Wu SJ, et al. Atrial gap junctions, NF-kappaB and fibrosis in patients undergoing coronary artery bypass surgery: the relationship with postoperative atrial fibrillation. Cardiology (2008) 112:81–88.[Web of Science][Medline]
  57. Takeuchi S, Akita T, Takagishi Y, Watanabe E, Sasano C, Honjo H, et al. Disorganization of gap junction distribution in dilated atria of patients with chronic atrial fibrillation. Circ J (2006) 70:575–582.[CrossRef][Web of Science][Medline]
  58. Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, et al. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart (2005) 91:166–170.[Abstract/Free Full Text]
  59. Wilhelm M, Kirste W, Kuly S, Amann K, Neuhuber W, Weyand M, et al. Atrial distribution of connexin 40 and 43 in patients with intermittent, persistent, and postoperative atrial fibrillation. Heart Lung Circ (2006) 15:30–37.[CrossRef][Medline]
  60. Severs NJ, Rothery S, Dupont E, Coppen SR, Yeh HI, Ko YS, et al. Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc Res Tech (2001) 52:301–322.[CrossRef][Web of Science][Medline]
  61. Gutstein DE, Morley GE, Vaidya D, Liu F, Chen FL, Stuhlmann H, et al. Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation (2001) 104:1194–1199.[Abstract/Free Full Text]
  62. Dhein S, Krusemann K, Schaefer T. Effects of the gap junction uncoupler palmitoleic acid on the activation and repolarization wavefronts in isolated rabbit hearts. Br J Pharmacol (1999) 128:1375–1384.[CrossRef][Web of Science][Medline]
  63. Wiegerinck RF, van Veen TA, Belterman CN, Schumacher CA, Noorman M, de Bakker JM, et al. Transmural dispersion of refractoriness and conduction velocity is associated with heterogeneously reduced connexin43 in a rabbit model of heart failure. Heart Rhythm (2008) 5:1178–1185.[CrossRef][Web of Science][Medline]
  64. Akar FG, Spragg DD, Tunin RS, Kass DA, Tomaselli GF. Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy. Circ Res (2004) 95:717–725.[Abstract/Free Full Text]
  65. Tsai CF, Tai CT, Hsieh MH, Lin WS, Yu WC, Ueng KC, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation (2000) 102:67–74.[Abstract/Free Full Text]
  66. Nathan H, Gloobe H. Myocardial atrio-venous junctions and extensions (sleeves) over the pulmonary and caval veins. Anatomical observations in various mammals. Thorax (1970) 25:317–324.[Abstract/Free Full Text]
  67. Saito T, Waki K, Becker AE. Left atrial myocardial extension onto pulmonary veins in humans: anatomic observations relevant for atrial arrhythmias. J Cardiovasc Electrophysiol (2000) 11:888–894.[Web of Science][Medline]
  68. Arora R, Verheule S, Scott L, Navarrete A, Katari V, Wilson E, et al. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation (2003) 107:1816–1821.[Abstract/Free Full Text]
  69. Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, et al. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation (2002) 105:2442–2448.[Abstract/Free Full Text]
  70. Cheung DW. Electrical activity of the pulmonary vein and its interaction with the right atrium in the guinea-pig. J Physiol (1981) 314:445–456.[Abstract/Free Full Text]
  71. Masani F. Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study. J Anat (1986) 145:133–142.[Web of Science][Medline]
  72. Verheule S, van Kempen MJ, Postma S, Rook MB, Jongsma HJ. Gap junctions in the rabbit sinoatrial node. Am J Physiol Heart Circ Physiol (2001) 280:H2103–H2115.[Abstract/Free Full Text]
  73. Blom NA, Gittenberger-de Groot AC, Jongeneel TH, DeRuiter MC, Poelmann RE, Ottenkamp J. Normal development of the pulmonary veins in human embryos and formulation of a morphogenetic concept for sinus venosus defects. Am J Cardiol (2001) 87:305–309.[CrossRef][Web of Science][Medline]
  74. Blom NA, Gittenberger-de Groot AC, DeRuiter MC, Poelmann RE, Mentink MM, Ottenkamp J. Development of the cardiac conduction tissue in human embryos using HNK-1 antigen expression: possible relevance for understanding of abnormal atrial automaticity. Circulation (1999) 99:800–806.[Abstract/Free Full Text]
  75. Mommersteeg MT, Brown NA, Prall OW, Gier-de Vries C, Harvey RP, Moorman AF, et al. Pitx2c and Nkx2–5 are required for the formation and identity of the pulmonary myocardium. Circ Res (2007) 101:902–909.[Abstract/Free Full Text]
  76. Sun Q, Tang M, Pu J, Zhang S. Pulmonary venous structural remodeling in a canine model of chronic atrial dilation due to mitral regurgitation. Can J Cardiol (2008) 24:305–308.[Web of Science][Medline]
  77. Zhang W, Ma X, Zhong M, Zheng Z, Li L, Wang Z, et al. Role of the calpain system in pulmonary vein connexin remodeling in dogs with atrial fibrillation. Cardiology (2008) 112:22–30.[CrossRef][Web of Science][Medline]
  78. Spach MS, Barr RC, Jewett PH. Spread of excitation from the atrium into thoracic veins in human beings and dogs. Am J Cardiol (1972) 30:844–854.[CrossRef][Web of Science][Medline]
  79. Zipes DP, Knope RF. Electrical properties of the thoracic veins. Am J Cardiol (1972) 29:372–376.[CrossRef][Web of Science][Medline]
  80. Yeh HI, Lai YJ, Lee SH, Lee YN, Ko YS, Chen SA, et al. Heterogeneity of myocardial sleeve morphology and gap junctions in canine superior vena cava. Circulation (2001) 104:3152–3157.[Abstract/Free Full Text]
  81. Kwong KF, Schuessler RB, Green KG, Laing JG, Beyer EC, Boineau JP, et al. Differential expression of gap junction proteins in the canine sinus node. Circ Res (1998) 82:604–612.[Abstract/Free Full Text]
  82. Chen YJ, Chen YC, Yeh HI, Lin CI, Chen SA. Electrophysiology and arrhythmogenic activity of single cardiomyocytes from canine superior vena cava. Circulation (2002) 105:2679–2685.[Abstract/Free Full Text]
  83. Lee SH, Chen YJ, Tai CT, Yeh HI, Cheng JJ, Hung CR, et al. Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing. Basic Res Cardiol (2005) 100:14–21.[CrossRef][Web of Science][Medline]
  84. Spach MS, Kootsey JM, Sloan JD. Active modulation of electrical coupling between cardiac cells of the dog. A mechanism for transient and steady state variations in conduction velocity. Circ Res (1982) 51:347–362.[Abstract/Free Full Text]
  85. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med (1997) 336:905–911.[Abstract/Free Full Text]
  86. Ellinor PT, Petrov-Kondratov VI, Zakharova E, Nam EG, MacRae CA. Potassium channel gene mutations rarely cause atrial fibrillation. BMC Med Genet (2006) 7:70.[CrossRef][Medline]
  87. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet (2006) 15:2185–2191.[Abstract/Free Full Text]
  88. Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, et al. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet (2004) 75:899–905.[CrossRef][Web of Science][Medline]
  89. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science (2003) 299:251–254.[Abstract/Free Full Text]
  90. Fox CS, Parise H, D'Agostino RB Sr, Lloyd-Jones DM, Vasan RS, Wang TJ, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA (2004) 291:2851–2855.[Abstract/Free Full Text]
  91. Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA. Familial aggregation in lone atrial fibrillation. Hum Genet (2005) 118:179–184.[CrossRef][Web of Science][Medline]
  92. Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H, et al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J (2006) 27:708–712.[Abstract/Free Full Text]
  93. Chen LY, Herron KJ, Tai BC, Olson TM. Lone atrial fibrillation: influence of familial disease on gender predilection. J Cardiovasc Electrophysiol (2008) 19:802–806.[CrossRef][Web of Science][Medline]
  94. Marcus GM, Smith LM, Vittinghoff E, Tseng ZH, Badhwar N, Lee BK, et al. A first-degree family history in lone atrial fibrillation patients. Heart Rhythm (2008) 5:826–830.[CrossRef][Web of Science][Medline]
  95. Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, et al. Renin–angiotensin system gene polymorphisms and atrial fibrillation. Circulation (2004) 109:1640–1646.[Abstract/Free Full Text]
  96. Lai LP, Su MJ, Yeh HM, Lin JL, Chiang FT, Hwang JJ, et al. Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J (2002) 144:485–490.[CrossRef][Web of Science][Medline]
  97. Chen LY, Ballew JD, Herron KJ, Rodeheffer RJ, Olson TM. A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther (2007) 81:35–41.[CrossRef][Web of Science][Medline]
  98. Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuijl L, et al. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res (2003) 92:14–22.[Abstract/Free Full Text]
  99. Firouzi M, Ramanna H, Kok B, Jongsma HJ, Koeleman BP, Doevendans PA, et al. Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ Res (2004) 95:e29–e33.[Abstract/Free Full Text]
  100. Juang JM, Chern YR, Tsai CT, Chiang FT, Lin JL, Hwang JJ, et al. The association of human connexin 40 genetic polymorphisms with atrial fibrillation. Int J Cardiol (2007) 116:107–112.[CrossRef][Web of Science][Medline]
  101. Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med (2006) 354:2677–2688.[Abstract/Free Full Text]
  102. Brundel BJ, Ke L, Dijkhuis AJ, Qi X, Shiroshita-Takeshita A, Nattel S, et al. Heat shock proteins as molecular targets for intervention in atrial fibrillation. Cardiovasc Res (2008) 78:422–428.[Abstract/Free Full Text]
  103. Sarrazin JF, Comeau G, Daleau P, Kingma J, Plante I, Fournier D, et al. Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs. J Am Coll Cardiol (2007) 50:1505–1512.[Abstract/Free Full Text]
  104. Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, et al. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res (2000) 87:656–662.[Abstract/Free Full Text]
  105. Chen HH, Baty CJ, Maeda T, Brooks S, Baker LC, Ueyama T, et al. Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation. Circulation (2004) 110:2980–2987.[Abstract/Free Full Text]
  106. Duthe F, Dupont E, Verrecchia F, Plaisance I, Severs NJ, Sarrouilhe D, et al. Dephosphorylation agents depress gap junctional communication between rat cardiac cells without modifying the Connexin43 phosphorylation degree. Gen Physiol Biophys (2000) 19:441–449.[Web of Science][Medline]
  107. Duthe F, Plaisance I, Sarrouilhe D, Herve JC. Endogenous protein phosphatase 1 runs down gap junctional communication of rat ventricular myocytes. Am J Physiol Cell Physiol (2001) 281:C1648–C1656.[Abstract/Free Full Text]
  108. van Rijen HV, van Veen TA, Hermans MM, Jongsma HJ. Human connexin40 gap junction channels are modulated by cAMP. Cardiovasc Res (2000) 45:941–951.[Abstract/Free Full Text]
  109. Kjolbye AL, Knudsen CB, Jepsen T, Larsen BD, Petersen JS. Pharmacological characterization of the new stable antiarrhythmic peptide analog Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2 (ZP123): in vivo and in vitro studies. J Pharmacol Exp Ther (2003) 306:1191–1199.[Abstract/Free Full Text]
  110. Grover R, Dhein S. Structure-activity relationships of novel peptides related to the antiarrhythmic peptide AAP10 which reduce the dispersion of epicardial action potential duration. Peptides (2001) 22:1011–1021.[CrossRef][Web of Science][Medline]
  111. Dhein S, Manicone N, Muller A, Gerwin R, Ziskoven U, Irankhahi A, et al. A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. A mapping study. Naunyn Schmiedebergs Arch Pharmacol (1994) 350:174–184.[Web of Science][Medline]
  112. Kjolbye AL, Holstein-Rathlou NH, Petersen JS. Anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-Ala-Gly-OH reduces dispersion of action potential duration during ischemia/reperfusion in rabbit hearts. J Cardiovasc Pharmacol (2002) 40:770–779.[CrossRef][Medline]
  113. Muller A, Schaefer T, Linke W, Tudyka T, Gottwald M, Klaus W, et al. Actions of the antiarrhythmic peptide AAP10 on intercellular coupling. Naunyn Schmiedebergs Arch Pharmacol (1997) 356:76–82.[CrossRef][Medline]
  114. Muller A, Gottwald M, Tudyka T, Linke W, Klaus W, Dhein S. Increase in gap junction conductance by an antiarrhythmic peptide. Eur J Pharmacol (1997) 327:65–72.[CrossRef][Web of Science][Medline]
  115. Eloff BC, Gilat E, Wan X, Rosenbaum DS. Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction: evidence supporting a novel target for antiarrhythmic therapy. Circulation (2003) 108:3157–3163.[Abstract/Free Full Text]
  116. Clarke TC, Thomas D, Petersen JS, Evans WH, Martin PE. The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43. Br J Pharmacol (2006) 147:486–495.[CrossRef][Web of Science][Medline]
  117. Xing D, Kjolbye AL, Nielsen MS, Petersen JS, Harlow KW, Holstein-Rathlou NH, et al. ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol (2003) 14:510–520.[CrossRef][Web of Science][Medline]
  118. Haugan K, Miyamoto T, Takeishi Y, Kubota I, Nakayama J, Shimojo H, et al. Rotigaptide (ZP123) improves atrial conduction slowing in chronic volume overload-induced dilated atria. Basic Clin Pharmacol Toxicol (2006) 99:71–79.[CrossRef][Web of Science][Medline]
  119. Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan JK, Nattel S. Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation (2007) 115:310–318.[Abstract/Free Full Text]
  120. Rossman EI, Liu K, Morgan GA, Swillo RE, Krueger JA, Butera J, et al. The gap junction modifier, GAP-134, improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model. J Pharmacol Exp Ther (2009) 329:1127–1133.[Abstract/Free Full Text]
  121. Haugan K, Olsen KB, Hartvig L, Petersen JS, Holstein-Rathlou NH, Hennan JK, et al. The antiarrhythmic peptide analog ZP123 prevents atrial conduction slowing during metabolic stress. J Cardiovasc Electrophysiol (2005) 16:537–545.[CrossRef][Web of Science][Medline]
  122. Dhein S, Polontchouk L, Salameh A, Haefliger JA. Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. Biol Cell (2002) 94:409–422.[CrossRef][Web of Science][Medline]
  123. Herve JC, Dhein S. Pharmacology of cardiovascular gap junctions. Adv Cardiol (2006) 42:107–131.[Web of Science][Medline]
  124. Salameh A, Dhein S. Pharmacology of gap junctions. New pharmacological targets for treatment of arrhythmia, seizure and cancer? Biochim Biophys Acta (2005) 1719:36–58.[Medline]
  125. Morley GE, Vaidya D, Samie FH, Lo C, Delmar M, Jalife J. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol (1999) 10:1361–1375.[Web of Science][Medline]
  126. van Rijen HV, Eckardt D, Degen J, Theis M, Ott T, Willecke K, et al. Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation (2004) 109:1048–1055.[Abstract/Free Full Text]
  127. Cha TJ, Ehrlich JR, Zhang L, Shi YF, Tardif JC, Leung TK, et al. Dissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure. Circulation (2004) 109:412–418.[Abstract/Free Full Text]

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