Abstract
Congenital heart disease (CHD) is the most common birth defect, affecting ~1% of all live births (van der Linde et al., 2011). Despite improvements in clinical care, it is the leading cause of infant mortality related to birth defects (Yang et al., 2006) and burdens survivors with significant morbidity (Gilboa et al., 2016). Furthermore, CHD accounts for the largest proportion (26.7%) of birth defect-associated hospitalization costs—up to $6.1 billion in 2013 (Arth et al., 2017). Yet after decades of research with a primary focus on genetic etiology, the underlying cause of these defects remains unknown in the majority of cases (Zaidi and Brueckner, 2017). Unexplained CHD may be secondary to undiscovered roles of noncoding genetic, epigenetic, and environmental factors, among others (Russell et al., 2018). Population studies have recently demonstrated that pregnancies complicated by CHD also carry a higher risk of developing pathologies associated with an abnormal placenta including growth disturbances (Puri et al., 2017), preeclampsia (Auger et al., 2015; Brodwall et al., 2016), preterm birth (Laas et al., 2012), and stillbirth (Jorgensen et al., 2014). Both the heart and placenta are vascular organs and develop concurrently; therefore, shared pathways almost certainly direct the development of both. The involvement of placental abnormalities in congenital heart disease, whether causal, commensurate or reactive, is under investigated and given the common developmental window and shared developmental pathways of the heart and placenta and concurrent vasculature development, we propose that further investigation combining clinical data, in vitro, in vivo, and computer modeling is fundamental to our understanding and the potential to develop therapeutics.
Highlights
Reviewed by: Alina Maloyan, Oregon Health & Science University, United States Bjarke Jensen, University of Amsterdam, Netherlands Consolato Sergi, University of Alberta Hospital, Canada
Population studies have recently demonstrated that pregnancies complicated by Congenital heart disease (CHD) carry a higher risk of developing pathologies associated with an abnormal placenta including growth disturbances (Puri et al, 2017), preeclampsia (Auger et al, 2015; Brodwall et al, 2016), preterm birth (Laas et al, 2012), and stillbirth (Jorgensen et al, 2014)
The involvement of placental abnormalities in congenital heart disease, whether causal, commensurate or reactive, is under investigated and given the common developmental window and shared developmental pathways of the heart and placenta and concurrent vasculature development, we propose that further investigation combining clinical data, in vitro, in vivo, and computer modeling is fundamental to our understanding and the potential to develop therapeutics
Summary
The heart and placenta develop concurrently, with heart tube specification occurring at days 16–21 and a rudimentary villous tree forming by day 21 of gestation (Schleich, 2002; Kaufmann et al, 2004; Khong, 2004; Linask, 2013; Tyser et al, 2016). Vascularization of the human placenta occurs by local de-novo vasculogenesis within the mesenchymal core of the secondary villi. This occurs prior to infiltration of fetal vessels or blood into the placenta with the progenitor cells derived directly from placental mesenchymal cells (Demir et al, 1989). The respective receptors, Flt-1 and Flk-1 are expressed on the vasculogenic and angiogenic precursor cells (Charnock-Jones et al, 2004) With this constellation an increase in the expression of VEGF and its receptors may orchestrate the temporal and spacial regulation of the differentiation and maturation of villous vascularization (Castellucci et al, 2000; Kingdom et al, 2000). Once established, signaling between the placenta and fetal organs via the fetal-placental circulation may impact growth and remodeling of both the fetal heart and the placenta, which, in the placenta occurs throughout gestation until term (Figure 2)
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