title: A mouse model to study the link between hypoxia, long QT interval and sudden infant death syndrome.
abstract: The pathology of sudden infant death syndrome (SIDS) is poorly understood. Many risk factors, including hypoxia, have been identified. Prolongation of the ECG QTc interval is associated with elevated risk of SIDS but its aetiology in most cases remains unknown. We have characterised ECG changes in the newborn mouse in the hours and days following birth. There was a steady increase in heart rate alongside significant decreases in QTc interval, QRS duration and QTc dispersion over the first 10 postnatal days. Birth into hypoxia (10% FiO2) prevented electrocardiac maturation, downregulated cardiac ion-channel expression and led to neonatal death. We found that risk of death decreased with increasing age of exposure to hypoxia. Genetic elevation of cardiac hypoxia-signalling after birth in αMHC-Cre::VHL(fl/fl) mice also prevented electrocardiographic maturation, leading to arrhythmia and death before weaning. Immunohistochemistry and western blotting revealed internalisation and dephosphorylation of Connexin43. We conclude that increased ambient oxygen concentration after birth drives maturation of the cardiac electrical conduction system, failure of which leads to aberrant ion channel and Connexin43 expression and predisposes to arrhythmia and sudden death. This is consistent with known risk factors of SIDS and provides a link between neonatal hypoxia, ECG abnormalities and sudden death.
authors.affiliation: Developmental Biology, MRC National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Marianne T
authors.initials: MT
authors.lastname: Neary
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mohun
authors.forename: Ross A
authors.initials: RA
authors.lastname: Breckenridge
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D055724:Electrophysiological Phenomena; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology; D007223:Infant; D019426:Integrases / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008133:Long QT Syndrome / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012307:Risk Factors; D013398:Sudden Infant Death / Q000473:pathology*; D014463:Ultrasonography
chemical_list: D018031:Connexin 43; D007473:Ion Channels; C045073:Cre recombinase; D019426:Integrases