INTRODUCTION: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic condition defined by episodic syncope that occurs during intense emotion or exercise. CPVT is usually caused by mutations in the cardiac ryanodine receptor (RyR2) gene, and while some patients remain asymptomatic into adulthood, others develop the disease during childhood, which suggests environmental factors can influence disease progression. However, to our knowledge, no one has considered the role of the maternal environment in programming CPVT outcomes.  Recent data from our laboratory suggests that ventricular arrhythmia sensitivity can be programmed during fetal development by exposure to hypoxia.  Therefore, we hypothesised that fetal hypoxia increases disease severity in individuals with a CPVT mutation.

METHOD: RyR2-R2474S knock-in male mice were bred with wild-type C57BL/6NRj female mice. Pregnant mice were either subjected to normoxic (21% O₂, n = 10) or hypoxic (13% O₂, n = 5) conditions from gestational day (GD) 6-18. From this experimental design, four groups were established – (1) Wild Type Normoxia (WT-N), (2) RyR2 normoxia (RyR2-N), (3) Wild Type Hypoxia (WT-H) and (4) RyR2 Hypoxia (RyR2-H). Maternal weight, food and water intake were monitored during the incubations, as well as offspring litter size, sex split and body weight from birth to 16 weeks.  Ventricular electrical mapping was used to investigate offspring arrhythmia sensitivity at 16 weeks using programmed electrical stimulation. 

RESULT: There were no significant differences in maternal body weight, food intake or water intake between the normoxic and hypoxic offspring. Furthermore, no significant relationship was found between litter size, sex split, individual offspring body weight, and litter weight between the experimental groups. The initial data suggests that fetal hypoxia and CPVT mutation both increase the likelihood of arrhythmia under programmed electrical stimulation, but there was no significant interaction between these factors. 

CONCLUSION: At this preliminary stage, we show that hypoxia had no significant effect on maternal and fetal parameters in either wild-type or CPVT mutants, suggesting no overt morphological effects of either treatment. The electrical mapping showed that arrhythmia sensitivity is increased by fetal hypoxia or CPVT mutation, but no interaction was observed between these factors.  However, data should be interpreted cautiously because of a low sample size (n = 4-7 offspring).  Therefore, future work will increase the sample size to fully ascertain whether exposure to fetal hypoxia can influence cardiovascular outcomes in CPVT mutants.