The heart does not simply need to grow. It needs to grow in the right place, at the right time, for the right duration.
In a preprint study published in Nature Communications in January, researchers from Adelaide University found that some cells had a previously unrecognised role in coordinating the growth and structure of the developing heart.
The study also sheds light on the potential origins of congenital heart disease.
Precise Control in Heart Development
At the centre of the discovery is NEDD4, a protein that acts as a molecular “quality control” system.
NEDD4 monitors and keeps another protein known as DKK1 under control; DKK1 acts as a brake on the “Wnt signalling pathway.”
The “Wnt signalling pathway” plays an important role in heart development by keeping heart’s “progenitor” cells (cells that mature into different types of heart cells, such as muscle and blood vessels) in a “ready-to-grow” state until it is time to mature into heart muscle.
Using mice, researchers found that those with dysfunctional NEDD4 had high levels of DKK1.
This prematurely shuts down the “Wnt signalling pathway,” causing the heart muscle to develop when it is not supposed to. As a result, the heart vessels and valves are shortened and misaligned, a hallmark of several serious congenital heart defects.
Researchers also found that “neural crest cells” supply the growing heart with DKK1.
These neural crest cells—which are found throughout the growing embryo and form part of the heart’s outflow tract—adjust how much DKK1 is present. This in turn fine-tunes and controls Wnt signalling in the heart’s “progenitor” cells, thereby allowing the heart’s vessels, specifically the outflow tract, to grow and lengthen correctly and at the right time.
When Timing Goes Wrong
Issues arise when the NEDD4 protein does not function properly.
For instance, when researchers reduced the levels of DKK1 in the mice, they could partially restore normal heart development.
It is important to note that results from animal experiments cannot be translated well into humans; however, in this study, the researchers had shown that removing NEDD4 from the neural crest cells resulted in heart outflow defects resembling those seen in children with Tetralogy of Fallot, one of the most common forms of congenital heart disease.
To prove this, the researchers found that a child with Tetralogy of Fallot had a mutation in the NEDD4 protein, which in turn reduced the ability to control DKK1 levels.
The findings also point to NEDD4 acting as a signalling hub that instructs how other cells behave.
“Heart development is an incredibly precise process,” the study’s lead author, Sophie Wiszniak from Adelaide University’s Centre for Cancer Biology (CCB), said in a media release.
“Cells need to stay in a flexible, immature state long enough for the heart to grow properly and then switch on muscle development at exactly the right moment. What we’ve discovered is a new way this balance is controlled.”
Management of Congenital Heart Disease
Errors in the heart development process are the leading cause of congenital heart disease. According to the Australian Institute of Health and Welfare, congenital heart disease affects around 9 in every 1000 infants globally and 2400 babies in Australia each year.
In the United States, heart defects affect nearly 1 percent of the population—or about 40,000 births per year, according to the U.S. Centers for Disease Control and Prevention (CDC).
Wiszniak told The Epoch Times that most defects are detected during routine prenatal ultrasound screenings during pregnancy. In severe cases, the heart may be treated using in utero surgery (performing surgery before the child is born) or surgery within the first months of life.
In milder cases, such as small septal defects or “holes in the heart,” doctors may opt for regular monitoring, as some defects can resolve naturally as the child grows.
For many patients, care continues throughout life. Children and adults with congenital heart disease are monitored through regular check-ups that include cardiac imaging such as echocardiograms, electrocardiograms, MRI scans and X-rays.
“Importantly, with advances in treatment, management and monitoring, most children these days survive into adulthood, and can expect to lead relatively normal lives,” Wiszniak said.
Clinical Significance
Despite advances in management, there is much more that is not understood. Wiszniak said that the causes of congenital heart defects remain unknown for up to 80 percent of cases.
“This points to the complexity of heart development, and how it can often go wrong.”
She told The Epoch Times that developing a stronger understanding of normal foetal heart development allows researchers and clinicians to piece together how and why the process can go wrong.
Senior author Quenten Schwarz added that by identifying the molecular pathway involved, scientists now have a clearer picture of how certain congenital heart defects arise.
The study provides preliminary evidence for a genetic cause of congenital heart disease, but Wiszniak cautions that more work needs to be done to confirm this.
“While there are curated lists of genes that are known to be associated with congenital heart defects, there are many additional unknown genes that likely also contribute,” Wiszniak said.
She added it was also difficult to classify whether genetic variants are “pathogenic” (causing disease) as there was not enough known about the genes’ role in disease.
“The more genetic variants we can identify in NEDD4 in other individuals, the more we can attribute this gene as a new causative factor of congenital heart disease.”
Future Works For Congenital Heart Disease
In the longer term, understanding how pathways such as Wnt signalling are regulated may guide the development of targeted therapies.
There is a precedent for this approach.
Wiszniak explained that researchers previously identified signalling pathways involved in patent ductus arteriosus (PDA), a form of congenital heart disease where a temporary blood vessel that does not close properly after birth. This understanding led to the use of drugs like aspirin and ibuprofen to treat the condition after birth.
Separate research by the University of New South Wales (UNSW) examined the role of gene “enhancers,” where researchers examined genes that are turned on and off, and how they contribute to heart development and disease, including congenital heart disease.
Although research is ongoing, current research results can contribute to the field of human genetics, more specifically, genetic counselling and diagnostics.