For most people, the heart鈥檚 electrical system works quietly in the background, coordinating each beat through the carefully timed movement of charged particles in and out of heart cells. But when part of that system fails, the consequences can be fatal.
Long QT syndrome is a disorder that can disrupt the heart鈥檚 normal rhythm and trigger potentially dangerous arrhythmias. Patients may experience heart palpitations or a fluttering sensation, but in severe cases, the abnormal rhythm can cause the heart to stop. The condition can emerge during childhood or early adulthood, and researchers continue to investigate why some people with genetic changes develop the disease while others do not.
For 91视频 College of Pharmacy (UHCOP) researcher Christian Egly, Pharm.D., Ph.D., assistant professor, that uncertainty represents an opportunity to better understand the disease at its molecular roots and potentially develop a more precise treatment. With a $526,284 National Heart, Lung, and Blood Institute grant, Egly鈥檚 research can take a deeper dive into this potentially fatal disease.
When Cellular Delivery System Breaks Down
At the center of Egly鈥檚 research is KV11.1, an ion channel that helps regulate the heart鈥檚 electrical activity. Ion channels act like microscopic passageways, allowing charged particles such as potassium, sodium and calcium to move through cell membranes and help maintain a normal heartbeat.
In many inherited cases of long QT syndrome, the problem begins before the channel ever reaches the cell surface.
Proteins must first be produced and folded into the correct shape before being transported to their proper location. Some genetic variants interfere with that process, leaving the KV11.1 protein trapped within a cellular structure called the endoplasmic reticulum rather than allowing it to reach the cell surface, where it performs its intended function.
Egly describes the failure as a 鈥渕is-trafficking event,鈥� a defect he hopes to address through targeted drug therapy.
Resulting from high-throughput drug screening conducted at his previous institution, Egly identified a drug candidate he described as having a 鈥渄ual effect鈥� in improving trafficking without blocking the channel while also upregulating channel activity. His current work is examining whether that approach could correct the biological mechanism underlying inherited long QT syndrome.
Sorting Through Thousands of Genetic Possibilities
Finding a potential drug is only one part of the challenge. Long QT syndrome is genetically complex.
Other researchers identified more than 500 variants among patients, while genetic testing continues to identify variants of unknown significance. For individuals carrying one of these uncertain variants, clinicians may not know whether it substantially increases the risk of an arrhythmia.
Egly鈥檚 project examines thousands of possible variants to determine which interfere with KV11.1 function and may respond to treatment.
By distinguishing harmful variants from those that function normally, Egly鈥檚 research could provide clinicians with better information about a patient's risk and treatment needs. The findings could eventually support a precision medicine approach in which an individual's genetic profile helps guide clinical decisions.
鈥淪uccess in this project would involve starting up a clinical trial, identifying what patients with long QT syndrome can be treated and getting a new medication approved for long QT syndrome,鈥� Egly said.
Bringing Patients Into the Lab
Egly is also incorporating induced pluripotent stem cells into the research, creating laboratory models derived from patient blood samples.
These renewable cell lines preserve a patient鈥檚 genetic background, allowing Egly to study the effects of different genetic factors over time. They also offer an alternative to murine models that may not fully reflect the complexity of human genetics.
鈥淣ow we can pull patient blood samples and make stem cell lines,鈥� Egly said. 鈥淥nce you have a stem cell line that鈥檚 reproducing, you can continue culturing it and derive numerous cell types such as neurons or heart cells for studies. These cells come directly from a patient and maintain all the genetic code of that individual.鈥�
By comparing cells derived from individuals at higher and lower risk of long QT syndrome, Egly hopes to uncover additional biological pathways that may influence susceptibility, including among people who do not carry well-established disease-causing variants.
Current therapies, he noted, generally manage the condition indirectly rather than correcting the underlying cellular defect.
The research may also have implications for drug-induced long QT syndrome, which occurs when certain medications interfere with the same ion channel. Egly is interested in whether similar strategies could prevent this effect, potentially allowing scientists to reconsider drug candidates previously abandoned because of cardiac risks.
At UHCOP, Egly will continue the work alongside new mentors Bradley McConnell, Ph.D., FAHA, UHCOP professor, and Mingfu Wu, Ph.D., UHCOP professor, while maintaining collaborations with his Vanderbilt mentors, Bjorn Knollmann, M.D., Ph.D., Vanderbilt University Medical Center professor, and Lars Plate, Ph.D., Vanderbilt University associate professor, extending a research effort that has occupied nearly eight years of his scientific career.
For patients whose risk may depend on a single genetic variation or a protein that never reaches its destination, Egly's research offers the possibility of a more targeted approach to treatment, one that could address the cellular defect responsible for the disease rather than its consequences alone.