Abnormal Cardiac Conduction and Morphogenesis in Connexin40 and Connexin43 Double-Deficient Mice

Connexin40-deficient (Cx40(-/-)/Cx43(+/+)) and connexin43-heterozygous knockout mice (Cx40(+/+)/Cx43(+/-)) are viable but show cardiac conduction abnormalities. The ECGs of adult double heterozygous animals (Cx40(+/-)/Cx43(+/-)) suggest additive effects of Cx40 and Cx43 haploinsufficiency on ventricular, but not on atrial, conduction. We also observed additive effects of both connexins on cardiac morphogenesis. Approximately half of the Cx40(-/-)/Cx43(+/+) embryos died during the septation period, and an additional 16% died after birth. The majority of the latter mice had cardiac hypertrophy in conjunction with common atrioventricular junction or a ventricular septal defect. All Cx40(-/-)/Cx43(+/-) progeny exhibited cardiac malformations and died neonatally. The most frequent defect was common atrioventricular junction with abnormal atrioventricular connection, which was more severe than that seen in Cx40(-/-)/Cx43(+/+) mice. Furthermore, muscular ventricular septal defects, premature closure of the ductus arteriosus, and subcutaneous edema were noticed in these embryos. Cx40(+/-)/Cx43(-/-) embryos showed the same phenotype (ie, obstructed right ventricular outflow tract) as reported for Cx40(+/+)/Cx43(-/-) mice. These findings demonstrate that Cx43 haploinsufficiency aggravates the abnormalities observed in the Cx40(-/-) phenotype, whereas Cx40 haploinsufficiency does not worsen the Cx43(-/-) phenotype. We conclude that the gap-junctional proteins Cx40 and Cx43 contribute to morphogenesis of the heart in an isotype-specific manner.