After 20 years of work,
UH researchers think they're close to
an answer for heart arrhythmia

By Helen Altonn
Star-Bulletin

Think of the heart as a complex Lego set of little protein machines.

Two University of Hawaii researchers have been trying for 20 years to figure out how they work -- or don't work in the case of arrhythmia, an abnormal heart rhythm that potentially can be fatal.

"We're down to a very small thing ... I think we have the beginnings of an answer," said Martin Rayner, professor of physiology in the Bekesy Laboratory of Neurobiology.

"In the next year or two, it will be found by us or some competitors."

Rayner and John Starkus are trying to solve the puzzle of channel molecules that control ion movements across the heart and muscle membranes.

By chance, they discovered that the potassium channels have a major role in regulating heartbeat.

They've been working with the Hawaiian fruit fly, Drosophila, which has a potassium channel similar to that of humans.

Rayner said the channel molecules are relatively unchanged after 2 billion years.

"They are so complicated, we suspect when we get to understand this mechanism we'll understand naturally occurring mutations producing increased arrhythmia in some persons and not in others," he said.

The amino acids, proteins, enzymes and muscles are all made of little Lego units, Rayner said. "They have different properties, yet somehow they make functional machines."

The channels have fast and slow inactivation mechanisms that open and close the channels like voltage switches, the scientists found.

They characterized the slow inactivation lever in a paper appearing in the November issue of the Journal of General Physiology.

"This is a big deal," Rayner said. "The heart relies on the slow inactivation system to determine the duration of contraction of the heart at each beat, so there is something really critical. "

With the slow inactivation mechanism, he said, channels that normally pass potassium "say 'no more.' They become potassium rejecting. We're on the edge of finding out why."

Potassium ions cause a contraction to stop, and when the flow is shut down, arrhythmia may occur, the scientists found.

Heart arrhythmia Arrhythmia (ah-rith-mee-ah) is an abnormal rhythm of the heart that can cause it to pump less effectively. It can be so brief that it is barely noticeable or it can cause the heart rate to be too slow or too fast. Types: Bradycardia (Bray-dee-kar-dee-ah) -- heart rate is less than 60 beats per minute; Tachycardia (Tak-ee-kar-dee-ah) -- heart rate is more than 100 beats per minute. Symptoms: Excessive slowing of the heartbeat can cause fatigue, dizziness, lightheadedness or fainting. Rapid heart beating, reducing the heart's ability to pump enough blood to the body, can cause shortness of breath, chest pain, lightheadedness and loss of consciousness. If severe, it can cause heart attack or death. Source: American Heart Association

The heart is a carefully regulated system, Rayner pointed out. "When it is beating slowly it needs time to fill and empty."

Starkus said there is an ion-regulated mechanism that seems to close the channel, but his work indicates "it seems to close the channel in a very unique way."

The channel doesn't physically close, but changes selectivity, he said. Some regulation won't allow potassium to pass through but will conduct other ions, such as calcium or sodium, he said.

Starkus speculated it's possible that the selectivity may involve some sort of calcium-potassium interaction.

The protein molecule has about 600 different amino acids in a DNA chain that regulates potassium channels. The UH scientists are creating mutations, trying to determine the function of each acid and its effect on ion flow.

"You could change selectivity quite dramatically by just changing one amino acid," Starkus said.

Pharmaceutical companies are interested in the work because it could lead to better drugs with fewer side effects, Rayner said.

He said UH is building a strong biomedical sciences group, working with researchers at The Queen's Medical Center and a collaborator at the Max Planck Institute in Germany.

The Hawaii group is in a race to make and characterize mutations, he said. "We're up against people who don't want us to play in their back yard."

The work has been supported entirely by the American Heart Association-Hawaii Affiliate and Queen Emma Foundation. New grants are being sought from the association and the National Institutes of Health.

Rayner said they've stepped up the research, with six graduate students involved in different projects.

"When you are this close to discovery, each step is insightful for other work. It's very hard, very exciting, and a lot of fun."