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

• Published in: Circulation research Vol. 87; no. 5; pp. 399 - 405
• Main Authors: Kirchhoff, Susanne, Kim, Jung-Sun, Hagendorff, Andreas, Thönnissen, Eva, Krüger, Olaf, Lamers, Wouter H, Willecke, Klaus
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.09.2000; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Animals; Animals, Newborn; Atrioventricular Node - abnormalities; Biological and medical sciences; Cardiomegaly - embryology; Connexin 43 - deficiency; Connexin 43 - physiology; Connexins - deficiency; Connexins - physiology; Crosses, Genetic; Electrocardiography; Embryo, Mammalian - pathology; Embryonic and Fetal Development; Fetal Heart - abnormalities; Fetal Heart - physiopathology; Fundamental and applied biological sciences. Psychology; Gap Junction alpha-5 Protein; Genotype; Gestational Age; Heart; Heart Conduction System - abnormalities; Heart Conduction System - physiopathology; Heart Septal Defects - embryology; Heart Valve Diseases - embryology; Mice; Mice, Knockout; Mortality; Phenotype; Vertebrates: cardiovascular system; Heart; Conduction; Deficiency; Rodentia; Transgenic animal; Heart ventricle; Gap junction; Morphogenesis; Connexin; Vertebrata; Mammalia; Mouse; Electrocardiography; Circulatory system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.87.5.399

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.