Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43double-deficient mice

Connexin40-deficient (Cx40(-/-)/Cx43(+/+)) and connexin43-heterozygous knoc kout mice (Cx40(+/+)/Cx43(+/-)) are viable but show cardiac conduction abno rmalities. The ECGs of adult double heterozygous animals (Cx40(+/-)/Cx43(+/ -)) suggest additive effects of Cx40 and Cx43 haploinsufficiency on ventric ular, but not on atrial, conduction. We also observed additive effects of b oth 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 i n conjunction with common atrioventricular junction or a ventricular septal defect. All Cx40(-/-)/Cx43(+/-) progeny exhibited cardiac malformations an d died neonatally. The most frequent defect was common atrioventricular jun ction with abnormal atrioventricular connection, which was more severe than that seen in Cx40(-/-)/Cx43(+/+) mice. Furthermore, muscular ventricular s eptal defects, premature closure of the ductus arteriosus, and subcutaneous edema were noticed in these embryos. Cx40(+/-)/Cx43(-/-) embryos showed th e same phenotype (ie, obstructed right ventricular outflow tract) as report ed for Cx40(+/+)/Cx43(-/-) mice. These findings demonstrate that Cx43 haplo insufficiency aggravates the abnormalities observed in the Cx40(-/-) phenot ype, whereas Cx40 haploinsufficiency does not worsen the Cx43(-/-) phenotyp e. We conclude that the gap-junctional proteins Cx40 and Cx43 contribute to morphogenesis of the heart in an isotype-specific manner.