Abstract
SUMMARYThe 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::VHLfl/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.
Highlights
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
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)
Heart rate increased whereas QRS, QTc and QTc dispersion declined rapidly and plateaued over the 24 hours (Fig. 1)
Summary
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. 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 Connexin (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
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