The role of connexin40 in atrial fibrillation

Abstract

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.

Connexin40 nonsense mutation in familial atrial fibrillation

“…However, functional changes in connexin40 alone could not be sufficient for the significantly prolonged P-wave duration, PQ interval, QRS duration, and QTc duration in the surface ECG, as was observed in a certain family, as well as in other patients (23,(33)(34)(35). In addition, in connexin40 knockout mice, the full deficiency in connexin40 was associated with altered ECG parameters, but in contrast, the haploinsufficiency for connexin40 was not (42). These findings imply that other factors combined with reduced coupling contribute to AF.…”

“…The targeted gene deletion of connexin40 in mice produced multiple abnormalities including increased sinoatrial node recovery time, decreased conduction velocity of the atria, atrioventricular node and bundle branch, and impaired sinoatrial propagation with atrial ectopic pacemakers, which developed arrhythmogenic substrate liable to AF (42,43). In a canine sterile pericarditis model, the gap junction conduction-enhancing anti-arrhythmic peptide, Gap-134, improved conduction and reduced AF (44).…”

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

“…However, functional changes in GJA5 alone may not be sufficient for significantly prolonged P-wave duration, PQ interval, QRS duration and QT duration in the surface electrocardiogram, as observed in these AF families and other AF patients (48)(49)(50)(51)(52)(53)(54)(55). Additionally, full deficiency for GJA5 has been associated with altered electrocardiographic parameters in GJA5 knockout mice, in contrast to haploinsufficiency for GJA5 (57). These findings suggest that additional factors combined with reduced coupling lead to AF.…”

“…The association of abnormal GJA5 with enhanced susceptibility to arrhythmias has been substantiated in animal models. Targeted gene deletion of GJA5 in mice produced multiple abnormalities including increased sinoatrial node recovery time, decreased conduction velocity of atria, atrioventricular node and bundle branch, and impaired sinoatrial propagation with atrial ectopic pacemakers, which developed an arrhythmogenic substrate prone to AF (57,58). In a canine sterile pericarditis model, the gap junction conduction-enhancing antiarrhythmic peptide, Gap-134, improved conduction and reduced AF (59).…”

Association between -44G/A and +71A/G polymorphisms in the connexin 40 gene and atrial fibrillation in Uyghur and Han populations in Xinjiang, China

“…The presence of an arrhythmogenic substrate and initiating triggers is known to determine vulnerability to heart arrhythmias. Initiating triggers of AF most often originate from firing foci in the pulmonary veins and/or superior cava vein (Chaldoupi et al, 2009). Long-term AF gives rise to electrical and structural remodeling that favor the reoccurrence or perpetuation of the condition.…”