SLOW VENTRICULAR CONDUCTION IN MICE HETEROZYGOUS FOR A CONNEXIN43 NULL MUTATION

To characterize the role of the gap junction protein connexin43 (Cx43) in ventricular conduction we studied hearts of mice with targeted del etion of the Cx43 gene. Mice homozygous for the Cx43 null mutation (CX 43 -/-) die shortly after birth. Attempts to record electrical activit y in neonatal Cx43 -/- hearts (n = 5) were unsuccessful. Ventricular e picardial conduction of paced beats, however, was 30% slower in hetero zygous (Cx43 -/+) neonatal hearts (0.14+/-0.04 m/s, n = 27) than in wi ld-type (Cx43 +/+) hearts (0.20+/-0.07 m/s, n = 32; P < 0.001). This p henotype was even more severe in adult mice; ventricular epicardial co nduction was 44% slower in 6-9 mo-old Cx43 -/+ hearts (0.18+/-0.03 m/s , n = 5) than in wild-type hearts (0.32+/-0.07 m/s, n = 7, P < 0.001). Electrocardiograms revealed significant prolongation of the QRS compl ex in adult Cx43 -/+ mice (13.4+/-1.8 ms, n = 13) compared with Cx43 /+ mice (11.5+/-1.4 ms, n = 12, P < 0.01). Whole-cell recordings of ac tion potential parameters in cultured disaggregated neonatal ventricul ar myocytes from Cx43 -/+ and +/+ hearts showed no differences. Thus, reduction in the abundance of a major cardiac gap junction protein thr ough targeted deletion of a Cx43 allele directly leads to slowed ventr icular conduction.