How blood flow shapes a forming heart

Evidence is growing that heart formation relies on mechanical signals generated by blood flowing through the developing heart, and not just genetics or environmental factors. The evidence for this intriguing idea was recently reviewed by scientists at ARMI.

Of babies born with a congenital defect, it is the heart that is​ ​most often impacted, especially the heart valves. It is striking that even today, the​ ​causes of these defects remain unknown in the majority​ ​of cases. 

In their review, recently published in MDPI journal Cells, group leader Dr Renee Chow and Masters student Anji Yang summarised accumulating evidence that may help solve why valve formation defects are so common.  

Anji explains that a rudimentary heart forms and begins contracting very early during embryonic development. In humans, this happens around Day 23. In the zebrafish – the model ARMI uses for its studies – a contracting heart tube is detectable within 24 hours after fertilisation. 

“Once the heart muscle forms, contractions start pumping blood and this generates biomechanical forces – such as wall shear, tensile and compressive stress – on the cells lining the heart,” Anji says.  

“A growing body of evidence is implicating these blood flow stresses in providing vital cues that guide valve development. These cues are envisioned as working alongside a genetic program that leads to the development of a fully formed, adult heart.” 

For the review into valve formation, Anji and Dr Chow examined the latest research undertaken in chicken eggs, zebrafish and mice.  

Early studies primarily explored valve formation in chicken eggs, using ink-based methods to visualise blood flow in the bloodstream. These studies implicated biomechanical forces in the expression of genes and the activation of receptors that are sensitive to mechanical stimuli. 

However, it is zebrafish that now lead the way in this field. 

Standout discoveries in zebrafish include the ability to interrupt valve formation by interrupting blood flow using pharmacological or microbead treatments. 

The impact of interrupted blood flow on valve formation has been captured in high-resolution videos​​ captured by Dr Chow. 

“Evidence generated at ARMI suggests a continuous role for mechanical forces and blood flow during valve formation,” Anji says. “We see that mechanical forces can influence signalling pathways that regulate how valve cells migrate and transition. For example, we can detect abnormal blood flow that disrupts valve formation in ways that lead to thick valves.” 

She notes, however, that the zebrafish heart is a lot simpler than a human heart. It has just one upper (atrium) and lower (ventricle) chamber, for instance. To better translate these findings to humans, complementary work is needed in mammalian models.  

The best model – especially when it comes to understanding developmental pathways in relation to genetic programs – is the murine model. This forms an important pivot point because the scientists ultimately envision an interplay between both blood flow forces and genetic mechanisms in instructing valve formation.  

The atrioventricular (AV) valves are located between the upper and lower heart chambers. They ensure unidirectional, forward blood flow and prevent backflow (regurgitation). The most common valve defect is regurgitation (when a valve does not close completely). Additional defects include stenosis (the narrowing or stiffening of the valve) and AV septal defects (the malformation of valves that can result in holes between right and left side sides of the heart).

If the picture holds in preclinical models – and then humans – then a way forward could emerge to account for cases where the heart defect is due to the valves. 

“Advances in imaging and experimental tools are now allowing us to study these biomechanical signals in much greater detail,” Anji says. 

The resulting insights may ultimately improve our understanding of heart development in ways that allow for better in utero detection and, someday, possibly, even improved surgical interventions.  

Set to benefit are half the babies born with a congenital heart defect who require surgical or catheter intervention to survive into adulthood. 

This research was supported by funding from the Estate of Donald G. Paech.