About 1% of all babies born each year in the United States are born with a congenital heart defect (CD), and the Centers for Disease Control and Prevention (CDC) report this number is increasing.
Despite the prevalence of coronary artery disease, it is poorly understood what causes these defects. But new research could provide insight into the genetic factors behind the problems, and researchers from Colombia University may have found a potential cure for one of them in a surprising source: an over-the-counter cough suppressant.
At Gladstone Institute of Data Science and Biotechnology in San Francisco, the researchers developed a new path identify genetic mutations that may play an important role in congenital heart disease. Deepak Srivastava, MD, president of Gladstone and principal 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 they contain – interact.
Srivastava and Pollard decided to focus on the GATA4 and TBX5 proteins, both of which are essential for healthy heart development. If these proteins are deformed, the resulting genetic changes almost always cause heart defects. By culturing precursor cardiac cells from human induced pluripotent stem cells, the researchers documented a total of 273 interactions between GATA4 and TBX5.
They then cross-referenced these interactions with the DNA data. Gladstone had a DNA sequencing database of over 3,000 children with congenital heart disease and their parents. By comparing protein interactions with DNA data, the researchers hoped to find links between certain protein interactions and heart defects.
To do this, researchers needed new tools. Maureen Pittman, a UCSF student working in Pollard’s lab, developed a computer program that ranked candidate proteins based on their likelihood of causing congenital heart disease. Pittman’s invention provided exactly the data they needed, including information about a protein called GLYR1, a gene that had never been linked to heart defects.
“Identifying GLYR1 as a key gene in heart development opens up a whole new biological space to understand how this system works. found us,” Srivastava said.
The data was published in the journal Cell in an article titled “Transcription factor protein interactomes reveal genetic determinants of heart disease.”
While Gladstone Institute researchers continue their work in San Francisco, a university across the country has a different approach to treating heart defects. AT Colombia Universityresearchers studying cardiac arrhythmia have discovered a potential new treatment: dextromethorphan, a cough suppressant.
In one article Posted in Nature Cardiovascular researchthe researchers explained that they were looking for treatments related to Timothy syndrome, a genetic condition in which the heart has unusually, and sometimes dangerously, long QT intervals between heartbeats.
In one previous study, Columbia researchers have found that increased activity of the CDK5 protein is linked to heart problems in Timothy syndrome. However, developing an inhibitor of the CDK5 protein is difficult without inhibiting other CDK proteins necessary for life.
In this latest study, the team tested a new treatment. They found that SIGMAR1, a non-opioid receptor, successfully shortened 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 drugs like Delsym, Robitussin and Mucinex, and it successfully activated the SIGMAR1 receptor in tests with mice.
By activating the SIGMAR1 receptor, dextromethorphan not only helped resolve many of the complications associated with Timothy syndrome, but it also helped relieve symptoms of long QT syndrome types I and II. This is because cardiac arrhythmias caused by cardiomyocytes have disrupted ion flows, which affects the flow of electricity needed for a regular heartbeat. Dextromethorphan helps regulate ion flow, helping to maintain regular heart rhythm for all three QT-related conditions.
Between these two studies, researchers are optimistic about the possibility of treatments for the high number of congenital heart defects.