scholarly journals Placental and fetal characteristics of the Ohia mouse line recapitulate outcomes in human hypoplastic left heart syndrome

2020 ◽  
Author(s):  
Rebecca L Wilson ◽  
Weston Troja ◽  
Jennifer Courtney ◽  
Helen N Jones
Keyword(s):  
Mouse Model ◽  
Mrna Expression ◽  
Hypoplastic Left Heart Syndrome ◽  
Fetal Growth ◽  
Fetal Weight ◽  
Left Heart ◽  
Heterozygous Genotype ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Left Heart Syndrome

AbstractCongenital heart defects (CHDs) are one of the most common birth defects worldwide. The morbidity and mortality associated with these defects is compounded by increased frequency of fetal growth abnormalities in the newborns. Inappropriate placental development and function has been implicated as a contributing factor to poor fetal growth in pregnancies complicated by CHDs however, the exact mechanisms are poorly understood. In the Ohia mouse model of hypoplastic left heart syndrome (HLHS), the double homozygous genotype had previously been shown to be embryonically lethal at mid-pregnancy; a time in which optimal establishment of the placenta is crucial to fetal survival. We aimed to characterize placental and fetal growth and development in the double heterozygous genotype to determine whether the genetic mutations associated with HLHS in the Ohia mouse also affect the placenta. The frequency of fetuses with reduced weight near term was shifted in the double heterozygous genotype compared to wildtype fetuses. This shift in fetal weight distribution was associated with reduced fetal capillary density in the placentas of the double heterozygotes as well as a reduction in placental mRNA expression of angiogenic factors placenta growth factor (Pgf) and fms-like tyrosine kinase-1 (Flt1) suggesting abhorrent placental angiogenesis. Positive correlations were observed between fetal weight and placenta mRNA expression of several nutrient transporters in the double heterozygous genotype but not observed in the wildtype. This data shows changes to placental angiogenesis and nutrient transport that are likely to contribute to inadequate fetal growth in the Ohia mouse model. Such differences are similar to findings in studies of human placentas from pregnancies with a fetus with HLHS and highlights the importance of this mouse model in continuing to understand the link between placental development and CHDs such as HLHS.New and NoteworthyWe used the Ohia mouse line, which is characterized with a hypoplastic left heart syndrome (HLHS)-like phenotype to investigate the contribution of placental development and function to fetal growth abnormalities associated with congenital heart defects (CHDs). We demonstrate an increase in the frequency of fetuses with lower fetal weight in the double heterozygous genotype which is associated with abnormalities to the placental microstructure, reduced placental fetal capillary density and placental mRNA expression of angiogenic factors Pgf and Flt1. These results are supported by similar studies of human placentas from HLHS pregnancies and highlights the usefulness of this model in furthering our understanding of abnormal fetal growth in CHDs.

scholarly journals Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries

2018 ◽  
Author(s):  
Weston Troja ◽  
Kathryn J. Owens ◽  
Jennifer Courtney ◽  
Andrea C. Hinton ◽  
Robert B. Hinton ◽  
...  
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Fetal Growth ◽  
Weight Ratio ◽  
Growth Patterns ◽  
Left Heart ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Terminal Villi ◽  
And Function ◽  
Left Heart Syndrome

AbstractBackgroundBirthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD.MethodsClinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Gene, analysis was performed using TopHat, R and MSigDB. Cluster analysis was performed using GoElite and Pathway analysis performed using PANTHERdb Overrepresentation Test. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups.ResultsPlacental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi, and increased fibrin deposition in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Need to include RNA and IHC.ConclusionsDespite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the

scholarly journals A mouse model of hypoplastic left heart syndrome demonstrating left heart hypoplasia and retrograde aortic arch flow

2021 ◽  
Author(s):  
Anum Rahman ◽  
Taylor DeYoung ◽  
Lindsay S. Cahill ◽  
Yohan Yee ◽  
Sarah K. Debebe ◽  
...  
Keyword(s):  
Mouse Model ◽  
Aortic Arch ◽  
Hypoplastic Left Heart Syndrome ◽  
Left Heart ◽  
High Frequency Ultrasound ◽  
Hypoplastic Left Heart ◽  
Fetal Abnormalities ◽  
Cardiac Phenotype ◽  
Disease Penetrance ◽  
Left Heart Syndrome

In hypoplastic left heart syndrome (HLHS), the mechanisms leading to left heart hypoplasia and their associated fetal abnormalities are largely unknown. Current animal models have limited utility in resolving these questions as they either do not fully reproduce the cardiac phenotype, do not survive to term, and/or have very low disease penetrance. Here, we report the development of a surgically-induced mouse model of HLHS that overcomes these limitations. Briefly, we microinjected the fetal left atrium of embryonic day (E) 14.5 mice with an embolizing agent under high-frequency ultrasound guidance, which partially blocks blood flow into the left heart and induces hypoplasia. At term (E18.5), all positively embolized mice exhibit retrograde aortic arch flow, non-apex forming left ventricles and hypoplastic ascending aortas. We thus report the development of the first mouse model of isolated HLHS with a fully penetrant cardiac phenotype and survival to term. Our method allows for the interrogation of previously intractable questions, such as determining the mechanisms of cardiac hypoplasia and fetal abnormalities observed in HLHS, as well as testing of mechanism-based therapies which are urgently lacking.

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