REDUCED CARDIAC CONDUCTION-VELOCITY AND PREDISPOSITION TO ARRHYTHMIASIN CONNEXIN40-DEFICIENT MICE

Intercellular channels of gap junctions are formed in vertebrates by t he protein family of connexins and allow direct exchange of ions, meta bolites 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 cel ls: atrial myocytes, cells of the atrial ventricular (AV) node and cel ls of the conductive myocardium, which conducts impulses from the AV n ode to ventricular myocyctes [3]. We have generated mice homozygous fo r targeted disruption of the Cx40 gene (Cx40(-/-) mice). The electroca rdiograph (ECG) parameters of Cx40(-/-) mice were very prolonged compa red to those of wild type (Cx40(+/+)) mice, indicating that Cx40(-/-) mice have lower atrial and ventricular conduction velocities, For 6 ou t of 31 Cx40(-/-) animals, different types of atrium derived abnormali ties in cardiac rhythm were recorded, whereas continuous sinus rhythm was observed for the 26 Cx40(+/+) and 30 Cx40(+/-) mice tested. The ex pression levels of other connexins expressed in heart (Cx37, Cx43 and Cx45) were the same in Cx40(-/-) and Cx40(+/+) mice. Our results demon strate the function of Cx40 in the regulation and coordination of hear t contraction and show that cardiac arrhythmogenesis can not only be c aused by defects in the ion channels primarily involved in cellular ex citation but also by defects in intercellular communication through ga p junction channels. As the distribution of Cx40 protein is similar in mouse and human hearts, further functional analysis of Cx40 should yi eld relevant insights into arrhythmogenesis in human patients.