VTCRI scientist awarded new federal grant to study cardiac conduction in health, disease

Steven Poelzing, an associate professor at the Virginia Tech Carilion Research Institute, has received a new five-year grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

The grant will fund Poelzing’s research into a heart mutation, known as a gain-of-function mutation, that can lead to sudden cardiac death and other heart conditions.

“It’s a less common mutation, but more lethal,” said Poelzing, who is also an associate professor in the Department of Biomedical Engineering and Mechanics in Virginia Tech’s College of Engineering. “With this mutation, the channels between the heart cells remain active when they shouldn’t.”

This specific mutation is concealed through puberty, and only becomes obvious after critical events in adolescence or early adulthood, such as unexplained fainting, seizures, or near drownings, according to the National Heart, Lung, and Blood Institute. The mutation frequently underlies Long QT syndrome, which can be inherited or acquired. On an electrocardiogram  reading, the length of time it takes for a heartbeat to drop from the peak to the baseline is referred to as QT. A long QT indicates an out-of-rhythm heartbeat.

“Something happens to cardiac cells during the maturation process that unmasks this mutation and makes it a dangerous problem,” Poelzing said. “If we can figure it out, we might be able to re-mask the mutation and keep the heart functioning properly.”

Heart cells communicate through channels called gap junctions. In childhood, cardiac cells are oval shaped, with gap junctions equally spaced around their borders. Adults have larger, brick-like cells with their gap junctions concentrated on the ends.

Poelzing, along with other researchers in the VTCRI Center for Heart and Regenerative Medicine, has found there is more to the story of conduction than cell size and gap junction location, though. There’s a parallel process of conduction called ephaptic coupling that doesn’t appear to rely on the direct channels of gap junctions to keep the heart in rhythm.

“It’s the difference between a cable and a spark,” Poelzing said. “Gap junctions allow direct communication, yet a person can lose 50 percent of them and not see a change in the electrical propagation properties of their heart. We discovered another mechanism of communication that helps maintain conduction even when gap junctions are lost.”

Sodium is crucial for the spark, according to Poelzing. The ephaptic coupling mechanism allows electrical current to jump the space between cardiac cells, even when the direct channel – the gap junction – isn’t working well or is even completely gone. Poelzing suspects that saline with different concentrations of sodium, potassium, and calcium can modulate the spark to help normalize conduction in different cardiac diseases.

“Salt water is a lifeline — often the first thing done for a patient in a hospital is give her a saline solution,” Poelzing said. “A different ratio of sodium in the saline may modulate cardiac conduction differently depending on the composition of the heart cells.”

That’s the subject of Poelzing’s first NHLBI grant. In that project, he focuses on how sodium affects conduction through both ephaptic coupling and gap junctions.

With his latest NIHLB grant, Poelzing is studying how mutated sodium channels can become over-activated causing major problems for the heart.

In both cases, problems can arise from miscommunication in the space between the cells and through the sodium channels acting as gatekeepers through the cellular membranes — especially if the channels have a gain-of-function mutation.

“One cell activates, and the sodium channels begin to drain the sodium ions from the space between them. The downstream channel wants to equalize, so it starts draining, too,” Poelzing said. “We end up with two large conducting channels continuously draining sodium out of the same space.”

In some mutated sodium channels, this over-activation can equalize to a point where the heart can function normally. Ephaptic coupling allows sodium to continue to seep from between cells, so it can empty in a way that allows a relatively regular beat.

That’s not always the case, though.

“Sodium boosting can be great, in some circumstances,” Poelzing said. “However, for people with this type of Long QT Syndrome, it could be catastrophic.”

When one channel opens, the reservoir of the cell needs to have some sodium to be stable. But if ephaptic coupling increases the intake of sodium, the flow goes for too long and the channels can’t reset.

“The channels between the heart cells remain active, and the heart never relaxes. It triggers another contraction across the muscle,” Poelzing said. “The typical check and balance of cardiac conduction disappears, and the cells become competitive when they should be working together.”

Each heartbeat triggers another in self-perpetuating waves, forcing the individual cells of the heart to work literally to death.

By understanding how the mutation triggers the sodium channels to continue draining while ephaptic coupling works to regulate sodium, the researchers may be able to target the levels of sodium so that even with the mutation, the channels may be able to reset and give the cells a chance to rest.

“It’s one small part of a very complicated system, but we might be able to make the sodium channels behave correctly, and that could reduce arrhythmias in people with gain-of-function diseases, such as heart failure,” Poelzing said. “Our hope is that our research will start to inform physicians on new strategies to prevent sudden cardiac death.”