Relationship Between Connexin Expression and Gap–Junction Resistivity in Human Atrial Myocardium

Background— The relative roles of the gap-junctional proteins connexin40 (Cx40) and connexin43 (Cx43) in determining human atrial myocardial resistivity is unknown. In addressing the hypothesis that changing relative expression of Cx40 and Cx43 underlies an increase in human atrial myocardial resistivity with age, this relationship was investigated by direct ex vivo measurement of gap-junctional resistivity and quantitative connexin immunoblotting and immunohistochemistry. Methods and Results— Oil-gap impedance measurements were performed to determine resistivity of the intracellular pathway ( R i), which correlated with total Cx40 quantification by Western blotting (rs=0.64, P <0.01, n=20). Specific gap-junctional resistivity ( R j) correlated not only with Western immunoquantification of Cx40 (rs=0.63, P =0.01, n=20), but also more specifically, with the Cx40 fraction localized to the intercalated disks on immunohistochemical quantification (rs=0.66, P =0.02, n=12). Although Cx43 expression showed no correlation with resistivity values, the proportional expression of the 2 connexins, (Cx40/[Cx40+Cx43]) correlated with R i and R j (rs=0.58, P <0.01 for R i and rs=0.51, P =0.02 for R j ). Advancing age was associated with a rise in R i (rs=0.77, P <0.0001), R j (rs=0.65, P <0.001, n=23), Cx40 quantity (rs=0.54, P =0.01, n=20), and Cx40 gap–junction protein per unit area of en face disk (rs=0.61, P =0.02, n=12). Conclusions— Cx40 is associated with human right atrial gap-junctional resistivity such that increased total, gap-junctional, and proportional Cx40 expression increases gap-junctional resistivity. Accordingly, advancing age is associated with an increase in Cx40 expression and a corresponding increase in gap-junctional resistivity. These findings are the first to demonstrate this relationship and a mechanistic explanation for changing atrial conduction and age-related arrhythmic tendency.