DISPARATE EFFECTS OF DEFICIENT EXPRESSION OF CONNEXIN43 ON ATRIAL ANDVENTRICULAR CONDUCTION - EVIDENCE FOR CHAMBER-SPECIFIC MOLECULAR DETERMINANTS OF CONDUCTION

Background-Myocardial conduction depends on intercellular transfer of current at gap junctions, Atrial myocytes express three different gap junction channel proteins-connexin43 (Cx43), connexin45 (Cx45), and co nnexin40 (Cx40)-whereas whereas ventricular myocytes express only Cx43 and Cx45. However, the physiological roles of individual connexins ar e unknown. previously shown that mice heterozygous for a null mutation in the gene encoding Cx43 (Cx43(+/-) mice) express 50% of the normal amount of Cx43 in ventricular myocardium and exhibit marked slowing of ventricular conduction. Methods and Results-To determine whether atri al conduction is affected in Cx43(+/-) mice, we measured atrial conduc tion velocity in isolated hearts, performed detailed ECG and electroph ysiological studies in intact animals, and determined the amount of ca rdiac connexins in atrial and ventricular tissue. Ventricular conducti on velocity was reduced by 38% in Cx43(+/-) mice compared with wild-ty pes, but atrial conduction velocity in the same hearts was normal. QRS duration was significantly greater in Cx43(+/-) mice than in wild-typ es, but P-wave duration and amplitude did not differ. Atrial expressio n of Cx43 was reduced by 50%. Conclusions-These results indicate that Cx43 is a principal conductor of intercellular current ill the ventric le because ventricular conduction is significantly slowed when Cx43 co ntent is reduced by only 50%. In contrast, a similar reduction in Cx43 content in atrial muscle has no effect on atrial conduction, suggesti ng that Cx40 (which is expressed in atrial but not ventricular myocyte s) is a major electrical coupling protein in atrial muscle, Thus, Cx43 and Cx40 may be chamber-specific determinants of myocardial conductio n.