Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice

Intercellular channels of gap junctions are formed in vertebrates by the protein family of connexins and allow direct exchange of ions, metabolites and second messenger molecules between apposed cells (reviewed in [1-3]), In the mouse, connexin40 (Cx40) protein has been detected in endothelial cells of lung and heart and in certain heart muscle cells: atrial myocytes, cells of the atrial ventricular (AV) node and cells of the conductive myocardium, which conducts impulses from the AV node to ventricular myocyctes [3]. We have generated mice homozygous for targeted disruption of the Cx40 gene (Cx40(-/-) mice). The electrocardiograph (ECG) parameters of Cx40(-/-) mice were very prolonged compared to those of wild type (Cx40(+/+)) mice, indicating that Cx40(-/-) mice have lower atrial and ventricular conduction velocities, For 6 out of 31 Cx40(-/-) animals, different types of atrium derived abnormalities in cardiac rhythm were recorded, whereas continuous sinus rhythm was observed for the 26 Cx40(+/+) and 30 Cx40(+/-) mice tested. The expression levels of other connexins expressed in heart (Cx37, Cx43 and Cx45) were the same in Cx40(-/-) and Cx40(+/+) mice. Our results demonstrate the function of Cx40 in the regulation and coordination of heart contraction and show that cardiac arrhythmogenesis can not only be caused by defects in the ion channels primarily involved in cellular excitation but also by defects in intercellular communication through gap junction channels. As the distribution of Cx40 protein is similar in mouse and human hearts, further functional analysis of Cx40 should yield relevant insights into arrhythmogenesis in human patients.