Introduction: Congenital heart disease (CHD) is the most common cause of neonatal morbidity and mortality, yet most cases remain idiopathic. Ventricular septal defects (VSDs) are the most prevalent type of CHD. Evidence in humans and mice suggests that VSDs frequently co-occur with abnormal placental development. These data imply that the placenta is an important factor in the aetiology of specific types of CHD. We hypothesize that certain placental defects will be associated with VSD and may in some cases cause this abnormality.
Methods: Mouse mutant lines selected from a phenotyping screen conducted by my lab will be used to explore mechanisms underpinning the placenta-heart axis. Heart and placental tissue will be assessed via microCT imaging, histological analysis and mRNA sequencing. In parallel, heart development will be modelled in vitro to identify the impact of placenta-secreted factors on cardiomyocyte differentiation.
Results: Analysis of mouse embryos mutant for the signal sequence receptor subunit 2 (Ssr2) revealed a tight correlation between the occurrence of VSDs and placental abnormalities, specifically affecting the placental labyrinth layer. In Ssr2 heterozygotes, VSD was still detected in 1 out of 6 embryos, reflecting either a developmental delay or haploinsufficiency with variable penetrance. MicroCT imaging is currently being optimized to include the placenta. This pipeline will then be utilized in other mutant mouse lines to establish whether common abnormalities exist in the placenta that can be tied to the aetiology of VSDs.
Conclusion: Specific placental abnormalities may be able to identify foetuses at risk of CHD. Importantly, understanding the developmental origins of CHD is a first step towards an earlier diagnosis of VSDs and ultimately for therapeutic intervention.
Rebecca Green– Post Doctoral Associate, University of Calgary
Benedikt Hallgrimsson– Department Head, Cell Biology & Anatomy, University of Calgary
Wendy Dean– Adjunct Professor, Alberta Children's Hospital Research Institute, University of Calgary
Myriam Hemberger– Professor, Alberta Children's Hospital Research Institute,University of Calgary
Bethany Radford– ACHRI/University of Calgary