Science for Health
12 September 2012
Researchers at NIMR have developed a new mouse model for Sudden Infant Death Syndrome. The research is published in Disease Models and Mechanisms.
Sudden Infant Death Syndrome (SIDS, or “cot death”) represents a substantial medical problem. Death rates have remained stubbornly high, at around 1 death in every 2000 apparently healthy infants making SIDS the leading cause of death in the first year of life after the neonatal period.
The pathology of SIDS is poorly understood. It is known that the majority of risk factors for SIDS are associated with low levels of oxygen in the newborn. The significance of this is controversial. Circumstantial evidence suggests a role for abnormal electrical conduction in SIDS, but the underlying cause(s) in the vast majority of cases remains unexplained. At the moment, there are no reliable animal models of SIDS, and very little information regarding the mechanism of death-why and how the babies die.
Because most risk factors for SIDS are associated with a reduced oxygen environment, Ross Breckenridge (pictured) and Marianne Neary, working in Tim Mohun’s lab in NIMR’s Division of Developmental Biology, hypothesised that neonatal hypoxia leading to abnormal electrical conduction was a potential cause of sudden death. They used non-invasive electrocardiography to characterize the postnatal maturation of the cardiac electrical conduction system in neonatal mice. They then investigated whether either reduced ambient oxygen environment or genetically manipulated hypoxic signalling would affect maturation of the cardiac electrical conduction system and subsequent risk of sudden death.
The researchers used a modified strain of mice with a genetically altered oxygen sensing system in their cells. The cells in the hearts of these mice, though born into a normal atmosphere, function as if they are in low-oxygen conditions. These genetically modified mice have the same ECG abnormalities that are known to be associated with infants at risk of SIDS. They found that risk of death decreased with increasing age of exposure to hypoxia. Genetic elevation of cardiac hypoxia-signalling after birth in the modified mice also prevented electrocardiographic maturation, leading to arrhythmia and death before weaning.
The researchers propose a model that links neonatal hypoxia with sudden death by cardiac arrhythmia by misregulation of cardiac Cx43 and ion channels.
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aMHC-Cre::VHLfl/fl mice, which are engineered to upregulate hypoxia signaling in the heart in normal levels of oxygen, show altered expression of the protein connexin43 (Cx43), which forms the pores connecting adjacent cardiomyocytes electrically. In control mice, Cx43 protein is located primarily at the call membrane (A i-iii) whereas in aMHC-Cre::VHLfl/fl hearts, it is internalised (A iv-vi). Overall levels of Cx43 are unaltered, but phosphorylation of Cx43 is significantly downregulated in aMHC-Cre::VHLfl/fl hearts (B). It is known that phosphorylation of Cx43 protein targets it to the plasma membrane, where it can form ion-conducting channels.
SIDS is a significant medical problem and we have very little clue of the disease mechanism. Our model is consistent with existing theories of SIDS pathogenesis, and links hypoxia, the major known risk factor for SIDS, with some of the important ECG changes seen in infants at risk of sudden death. The study suggests, for the first time, that there is a direct effect of oxygen levels on the myocardium of infants. This work should allow insight into the mechanism of SIDS, and the new mouse model of SIDS will allow further work on preventative treatments.
Hypoxia, Long QT interval and Sudden Infant Death Syndrome (SIDS) (2012)
Marianne T Neary, Timothy J Mohun, Ross A Breckenridge
Disease Models and Mechanisms Epub ahead of print. Publisher abstract
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