Fetal Blood Flow and Genetic Mutations in Conotruncal Congenital Heart Disease

Abstract

In congenital heart disease, the presence of structural defects affects blood flow in the heart and circulation. However, because the fetal circulation bypasses the lungs, fetuses with cyanotic heart defects can survive in utero but need prompt intervention to survive after birth. Tetralogy of Fallot and persistent truncus arteriosus are two of the most significant conotruncal heart defects. In both defects, blood access to the lungs is restricted or non-existent, and babies with these critical conditions need intervention right after birth. While there are known genetic mutations that lead to these critical heart defects, early perturbations in blood flow can independently lead to critical heart defects. In this paper, we start by comparing the fetal circulation with the neonatal and adult circulation, and reviewing how altered fetal blood flow can be used as a diagnostic tool to plan interventions. We then look at known factors that lead to tetralogy of Fallot and persistent truncus arteriosus: namely early perturbations in blood flow and mutations within VEGF-related pathways. The interplay between physical and genetic factors means that any one alteration can cause significant disruptions during development and underscore our need to better understand the effects of both blood flow and flow-responsive genes.

Hemodynamic and Structural Comparison of Human Fetal Heart Development Between Normally Growing and Hypoplastic Left Heart Syndrome-Diagnosed Hearts

“…CHDs’ etiology and causation still remain unclear ( Yalcin et al, 2011 ). Despite the fact that genetic factors play a significant role in the development of CHDs ( Jarrell et al, 2019 ; Dyer and Rugonyi, 2021 ), they are not the only cause of early cardiac disorders ( Zaidi et al, 2013 ; Rugonyi, 2016 ). For newborns, only 2–4% of CHDs are reported in the families with a history of CHDs, indicating that the majority of cases occur in newborns with no family history of early cardiac disorders ( Øyen et al, 2009 ).…”

Effect of Blood Flow on Cardiac Morphogenesis and Formation of Congenital Heart Defects

“…CHD manifests as one or more defects in a newborn's heart. The etiology of CHD is multifactorial, with several factors contributing to its risks [1,6,7]. Well known and relatively well-studied factors include embryonic genetic and epigenetic anomalies (e.g., the 22q11.2 deletion associated with DiGeorge syndrome), some maternal habits (e.g., smoking, alcohol, and recreational drug consumption), and maternal conditions (e.g., undernutrition, diabetes, infectious diseases).…”