New Research Offers Hope for Treating Congenital Heart Defects

The potential congenital heart defect treatment is here.

The potential congenital heart defects treatment is here. 

About 1% of all babies born each year in the United States are born with a congenital heart defects (CHD), and the Centers for Disease Control and Prevention (CDC) report that number is increasing.

Despite the prevalence of congenital heart defects, there is a poor understanding of what causes these defects. But new research may provide some insight into genetic factors that are causing the problems, and researchers at Columbia University may have found a potential treatment for one in a surprising source: over-the-counter cough suppressant.  

At the Gladstone Institute of Data Science and Biotechnology in San Francisco, researchers have developed a new way to identify genetic mutations that may play a significant role in congenital heart disease. Deepak Srivastava, M.D., president of Gladstone and senior investigator of the study, and Katie Pollard, Ph.D., director of Gladstone, took a unique approach in their research. Rather than looking at individual genes in isolation, they looked at how genes - and the proteins on them - interact. 

About the Treatment of Congenital Heart Defects

Srivastava and Pollard decided to focus on proteins GATA4 and TBX5, both of which are essential for healthy heart development. If these proteins experience malformations, the resulting genetic changes nearly always cause congenital heart defects. By growing precursor heart cells from human-induced pluripotent stem cells, the researchers documented a total of 273 interactions between GATA4 and TBX5.  

They then cross-referenced those interactions with DNA data. Gladstone had a bank of DNA sequencing data from over 3,000 children with congenital heart disease and their parents. By comparing the protein interactions with the DNA data, researchers hoped to find links between certain protein interactions and congenital heart defects.  

To do this, the researchers needed new tools. Maureen Pittman, a UCSF student working in Pollard’s lab, developed a computational program that ranked the protein candidates according to their likelihood of causing congenital heart disease. Pittman’s invention yielded exactly the data they needed, including insights into a protein called GLYR1, a gene that had never been linked to congenital heart defects.  

"Identifying GLYR1 as a key gene in heart development opens up a whole new biological space for understanding how this system works. We will continue to study the biology of GLYR1, and we hope that others will follow up on the other high-scoring variants we found," said Srivastava.  

The data  has been published in the journal Cell in an article titled "Transcription Factor Protein Interactomes Reveal Genetic Determinants in Heart Disease."

While the researchers at the Gladstone Institute continue with their work in San Francisco, a university on the other side of the country has a different approach to treating congenital heart defects. At Columbia University, researchers studying heart arrhythmia found a new potential treatment: dextromethorphan, a cough suppressant.  

In an article published in Nature Cardiovascular Research, researchers discussed that they were looking for treatments related to Timothy syndrome, a genetic disorder where the heart has unusually, and sometimes dangerously, long QT intervals between heartbeats.  

In a previous study, Columbia researchers found that increased activity of the CDK5 protein was linked with the cardiac problems of Timothy syndrome. However, developing an inhibitor of the CDK5 protein is difficult without inhibiting other CDK proteins that are necessary for life.

In this latest study, the team tested a new treatment. They found that SIGMAR1, a non-opioid receptor, successfully shortened the long QT heartbeat intervals. Activating SIGMAR1 was the tricky part, and they found a solution in dextromethorphan. The common cough suppressant is the main ingredient in medications like Delsym, Robitussin and Mucinex, and it successfully activated the SIGMAR1 receptor in tests on mice.  

By activating the SIGMAR1 receptor, not only did dextromethorphan help solve many complications associated with Timothy syndrome, but it also helped with symptoms of long QT syndrome types I and II. This is because heart arrhythmias caused by cardiomyocytes have disrupted flows of ions, which affects the flow of electricity needed for a regular heartbeat. Dextromethorphan helps regulate ion flow, helping keep the heartbeat regular for all three QT-related conditions.  

Between these two studies, researchers are optimistic about the possibility of treatments for the high numbers of congenital heart defects.

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