The Gap-Junctional Protein Connexin40 Is Elevated in Patients Susceptible to Postoperative Atrial Fibrillation

Abstract

Atrial myocardium susceptible to AF is distinguished from its nonsusceptible counterpart by elevated connexin40 expression. The heterogeneity of connexin distribution could give rise to different resistive properties and conduction velocities in spatially adjacent regions of tissue, which become enhanced and, hence, proarrhythmic the higher the overall level of connexin40.

Functional consequences of co-expressing connexin40 or connexin45 with connexin43 on intercellular electrical coupling

“…Chemicon, CA, USA), anti-Cx40 (SC-20466; Santa Cruz, CA, USA) and anti-Cx45 (Q14E MAB19-11-5; in-house) [12,13]. Labeled connexin protein was visualized using alkaline phosphatase-conjugated secondary antibody and an NBT/BCIP Liquid Substrate System (Sigma, MO, USA).…”

“…Gap junction channels directly link the internal environments of neighboring cardiac myocytes and therefore play a pivotal role in the direct cell-to-cell transfer of the electrical impulses which governs the coordinated contraction of the myocardium [9,10,12] Connexins are the principal components of gap junctions, and three members are expressed in cardiac myocytes: connexin43 (Cx43), connexin40 (Cx40) and connexin45 (Cx45). Disruption of gap junction distribution and remodeling of connexin expression are consistent features of human heart disease [29].…”

Is there a role for remodeled connexins in AF? No simple answers

“…Cx40 is expressed in high levels, 2 to 3 fold higher in the right atrium than the left [46]. It has been shown that the normal Cx40 distribution may also be heterogeneous with areas containing large amounts of Cx40 adjacent to others containing minimal or no Cx40 although hetrogeneities have not been precisely quantified [47][48][49]. The variable expression is likely to lead to inaccuracies in quantification of Cx40 in studies on remodeling in AF since only small samples of right atrial myocardium have been analyzed in most studies.…”

“…Due to the difficulty in detecting this connexin (in part due to high cross reactivity of some of the Cx45 antibodies) it has been difficult to determine how much Cx45 is in either normal or pathological atrial tissue although the levels appear to be much lower than either of the other two atrial connexins [46]. The impact of Cx45 on normal function or in atrial fibrillation is not known since it has not been measured in most studies (but see [47]). …”

“…Connexin quantification in left atrium has rarely been done [82,83]. Increased Cx40 [47,49,82,84], decreased Cx40 [49,54,85] and no change in Cx40 [54,83] have been reported. A common finding irrespective of quantitative changes in humans or animal models has been an increased heterogeneity in Cx40 distribution manifested as increased regions in which Cx40 containing myocytes are located adjacent to myocytes mostly lacking Cx40 [47,49,54,83,85,86].…”