Abstract 5321: An RyR2-R176Q Knock-In Mouse Model of Sudden Infant Death Syndrome
Introduction: Sudden infant death syndrome (SIDS) is a devastating occurrence that has multiple underlying causes. Recently, Tester et al. have shown that mutations in the cardiac ryanodine receptor (RyR2) may cause 10–20% of all arrhythmogenic death in victims of SIDS. We investigated the role of arrhythmic death in an RyR2-R176Q (R176Q) heterozygous knock-in neonatal mouse model.
Methods: The incidence of neonatal sudden death was monitored prospectively for 1.5 years in a colony of R176Q mice. Intra-cardiac programmed electrical stimulation (PES) was performed on 14–16 day old mice after intra-peritoneal injection of 0.5 mg/kg of isoproterenol to unmask a predisposition to ventricular arrhythmias. Hearts were stained with hematoxylin and eosin (HE) and Mason’s Trichrome (MT) to evaluate for structural abnormalities. Reverse transcriptase polymerase chain reaction (rt PCR) evaluated the expression of associated calcium handling proteins.
Results: Analysis shows a higher incidence of death in the R176Q mice with an 11.9% (18/151) vs. 7.8% (10/129), incidence of death compared to wild type mice. Proportionally more male mice compared to female mice died (61% vs. 39%). Heterozygous RyR2-R176Q mouse pups displayed an increased incidence of ventricular arrhythmias compared to wild types after intra-peritoneal isoproterenol injection during intra-cardiac PES. We found that 80% (4/5) R176Q mice developed arrhythmias after PES vs. only 20% (1/5) wild types. HE and MT staining reveals the absence of structural heart disease and rt PCR revealed no difference in expression levels of calcium handling proteins.
Conclusions: An increased incidence of mortality during infancy and ventricular arrhythmias following PES shows that RyR2-R176Q mice can be used as a model for elucidating cardiovascular mechanisms of SIDS. This model can be used to determine if acidosis, hypoxia, or fever accentuates vulnerability to SIDS. Additionally, this model may be used to investigate sex differences in arrhythmic death.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).