αMHC-Cre::VHLfl/fl mice have cardiac-specific deletion of von Hippel-Lindau protein (VHL), causing constitutive upregulation

Sudden infant death syndrome (SIDS) is death of an infant that is neither attributable to medical history nor explained after autopsy or by death scene investigation. SIDS is the leading cause of death in the first year of life after the neonatal period and is currently responsible for 0.53 deaths per 1000 infants. High incidence, catastrophic impact on affected families and absence of mechanistic insight means that SIDS represents a major medical challenge. Since the ‘back to sleep’ campaign in 1994, there have been no further reductions in SIDS incidence. A number of causative mechanisms have been proposed to lead to SIDS, but without any unifying theory or correlation with pathological findings (Goldwater, 2011). A study of 33,034 infants found that 50% of infants who died of SIDS had a prolonged QTc interval in the first week of life (Schwartz et al., 1998). Approximately 10% of SIDS cases carry functionally significant genetic variants in sodium and potassium channels causing long QT (Arnestad et al., 2007), or variants in the gap junction protein Connexin43 (Cx43) (Van Norstrand et al., 2012). This circumstantial evidence suggests a role for abnormal electrical conduction in SIDS, but the underlying cause(s) in the vast majority of cases remains unexplained. Most risk factors for SIDS, including prone sleeping position, respiratory disorders and high altitude, are associated with a reduced oxygen environment. Furthermore, hypoxia is associated with a prolonged QT interval in the adult (Roche et al., 2003; Tirlapur and Mir, 1982). We therefore hypothesised that neonatal hypoxia leading to abnormal electrical conduction is a potential cause of sudden death. We used non-invasive electrocardiography to characterize the postnatal maturation of the cardiac electrical conduction system in neonatal mice (Chu et al., 2001). We investigated whether reduced ambient oxygen environment or genetically manipulated hypoxic signalling affected maturation of the cardiac electrical conduction system and the subsequent risk of sudden death.