(AHA) The Placental Heart Interaction in CHD

Principal Investigator: Bob Silver
Keywords: Pregnancy , Congenital Heart Disease Department: Obstetrics And Gynecology (Dept)
IRB Number: 00104391 Co Investigator:  
Specialty: Maternal-Fetal Medicine
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Kelly Vorwaller
kelly.vorwaller@hsc.utah.edu
801-585-6996

Brief Summary

Specific Aims:

Congenital heart defects (CHD) are among the most frequent birth defects and remain an important cause of infant morbidity and mortality1-2. The prevalence and severity of CHD place an enormous burden on the health care system, and thus strategies to prevent CHD and improve outcomes could benefit many children and save billions of dollars in resource utilization. A major barrier to the prevention of CHD is uncertainty regarding its etiology. Despite strong evidence for a genetic basis, a genetic etiology is identified only in 20-30% of isolated CHD cases. We hypothesize that the maternal-fetal environment and CHD are intricately linked via the placenta and that unique epigenetic signatures are detectable in the maternal circulation, the placenta and fetus that provide insight into the etiology of CHD and predict clinical outcomes. Emerging evidence links placental function to cardiac development, the so-called heart-placenta axis3. For example, global deletion of p38𝛼-MAP kinase or PPAR-γ results in cardiac defects that are rescued by selective expression of these genes in the placenta4-5. Furthermore, impeding blood flow in utero recapitulates hypoplastic left heart syndrome (HLHS) in animal models6. As blood flow provided by the placental is the major determinant of early fetal cardiac output, early placental dysfunction might impact cardiac morphogenesis. Evidence in humans also supports the heart-placenta hypothesis. Abnormal placental angiogenesis is associated with conotruncal and septal defects7. Moreover, vascular and structural placental abnormalities indicative of placental immaturity have been reported in newborns with HLHS8. Our preliminary analyses confirm that many genes important in cardiac development are highly expressed in placenta and down regulated in placenta from Trisomy 21 patients, who as a group are at high risk for CHD.

The Developmental Origins of Health and Disease Theory posits that fetal adaptations to the in utero environment underlie the susceptibility to variety of childhood and adult diseases, mediated in part, via epigenetic alterations9. Emerging evidence supports the notion that epigenetic regulation of the placental transcriptome plays a crucial role not only in placental development, but also in mediating the effects of the intrauterine environment (e.g., smoking, diabetes, malnutrition) on the fetus itself. For example, differentially methylated DNA patterns in placenta from gestational diabetes correlated with fetal leukocyte DNA methylation, that in turn correlated with newborn weight10,11. These studies imply a degree of crosstalk between the placental and fetal epigenomes that has implications for fetal and newborn health. Throughout pregnancy, placental trophoblasts release extracellular vesicles into the maternal circulation that contain biologically active placenta-derived proteins and microRNAs (miRNAs), including miRNAs relevant to cardiovascular biology12. The repertoire of placenta-derived miRNAs in the maternal circulation and their relationship to adverse pregnancy outcomes is a subject of intense investigation, and these miRNAs may serve as biomarkers for adverse pregnancy outcomes. We hypothesize that mediators of placental function, circulating placenta-derived miRNAs, placenta DNA methylation and the placental transcriptome, are differentially altered in CHD versus control pregnancies, contribute to the etiology of CHD and influence clinical outcomes. We propose a prospective cohort-control study design to determine the relationships between placental function, epigenetics, CHD etiology and 1-year outcomes in a high-risk subset of infants with CHD. We will focus on epigenetic modifications and pathophysiologic pathways relevant to the heart-placenta axis, leveraging our multidisciplinary expertise in longitudinal obstetric studies, fetal-pediatric cardiology, genetics, epigenetics, and bioinformatics-systems biology.

Aim 1: Delineate epigenetic and transcriptomic signals that link the maternal-fetal environment with CHD. We will test the hypothesis that the heart-placenta axis is dysregulated in CHD versus control pregnancies. We propose that CHD pregnancies are associated with placental dysfunction as detected by alterations in circulating placenta-derived miRNAs, placenta DNA methylation patterns and the placental transcriptome. We will conduct a prospective cohort control study of pregnancies with antenatally diagnosed CHD and controls; N=360 in each group. Detailed anthropomorphic and obstetric data (maternal obesity, metabolism, blood pressure), environmental exposures (medications, smoking) as well as extensive biospecimens (maternal blood, cord blood, placenta) will be collected. Circulating placental-derived miRNAs, placental transcriptome, epigenome, histologic pathology, and fetal leukocyte epigenome will be analyzed. Novel bioinformatic tools developed by our collaborators at Universities of Utah and Pittsburgh will be used to uncover alterations in placental gene regulatory networks and epigenetic modifications in case control comparisons. Together with a systems biology approach, we will identify derangements in the heart-placenta axis that are associated with CHD.

Aim 2: Delineate epigenetic and transcriptomic signals derived from the maternal-fetal environment that influence outcomes in single ventricle CHD. Here, we explore the hypothesis that dysregulation of the heart-placenta axis during pregnancy impacts early survival, growth and developmental outcomes in infants with single ventricle CHD requiring neonatal surgical palliation. We focus on single ventricle CHD as this cohort has the highest morbidity and mortality of all complex CHD. We will follow the single ventricle cohort postnatally to 1 year of age with serial evaluation of growth, echocardiographic evaluation of ventricular function, and developmental outcomes. We will determine whether specific alterations in mediators of placental function from Aim 1 (circulating placenta-derived miRNAs, placenta DNA methylation patterns and the placental transcriptome) and the leukocyte epigenome correlate with the heterogeneity in clinical outcomes, focusing on gene regulatory networks relevant to each outcome using the bioinformatics pipeline in Aim 1. The results of this exploratory aim will inform larger studies of the contribution of the heart-placenta axis in the context of development reprogramming that modifies clinical outcomes in complex CHD.

This study is significant, as it will identify novel mechanisms associated with the development of CHD and pathways that adversely affect outcomes that may inform prevention. The proposal is innovative as it utilizes an unbiased, large data approach to characterize the complex relationships between the maternal-fetal environment and CHD etiology and outcomes. Accomplishing the aims of this proposal has tremendous implications for both the scientific knowledge of CHD and clinical practice, in that placental derived miRNAs might serve as biomarkers for early CHD detection and/or risk stratification.

Figure 4 - (Please see Documents and Attachments for Figures and Tables)

Hypothesis/Research Questions: (i.e., what exact questions do you hope to answer?)

Aim 1: Delineate epigenetic and transcriptomic signals that link the maternal-fetal environment with CHD.

Hypothesis: The heart-placenta axis is dysregulated in CHD versus control pregnancies and CHD pregnancies are associated with placental dysfunction detected by alterations in circulating placenta-derived miRNAs, placenta DNA methylation patterns and the placental transcriptome.

 

Aim 2: Delineate epigenetic and transcriptomic signals derived from the maternal-fetal environment that influence outcomes in single ventricle CHD.

Hypothesis: Dysregulation of the heart-placenta axis during pregnancy impacts early survival, growth and developmental outcomes in infants with single ventricle CHD requiring neonatal surgical pallia

 

Inclusion Criteria

Pregnant women age 18 and older.

Research staff will prioritize pregnant women 20-26 weeks gestation, but accept all gestational ages for case pregnancies with confirmed diagnosis of CHD and match controls accordingly. 

Aim 1:

Case Pregnancies:  Antenatally diagnosed CHD (Maternal = 360 / Paternal = 360)

Control Pregnancies:  Controls - Matched by gestational age to cases (n=360)

Aim 2:  

Infants from pregnancies with antenatally identified congenital heart disease with single ventricle physiology enrolled as Cases in Aim 1

Exclusion Criteria

Case Pregnancies: 

A normal post-natal echo

Infants with no surgical intervention planned

Controls:  Prior spontaneous preterm birth, multiple gestations, or known placental abnormality (e.g. Previa)