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Heart and Head Misfire Together

16 October 2009 (All day)
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A. Goldman et al., Science Translational Medicine

Double trouble. Brain neurons (green) with a faulty potassium channel. An EEG and an ECG show that epileptic seizures (top) often coincide with heart arrhythmias (bottom) in mice.

Two medical problems caused by misfiring electrical signals, epilepsy and heart arrhythmia, probably have a common molecular cause, scientists report. The research points to treatments that could lower the chances of young people dying of seizures.

The scientists, at Baylor College of Medicine in Houston, Texas, were studying mice that had a mutation in the KCNQ gene, which builds potassium ion channels that set up an action potential across a cell membrane. These channels help the heart beat by resetting the potential after cardiac muscle cells contract. The mutation--also found in humans--produces a faulty protein that delays restoration of the potential, causing erratic beating and sometimes death.

The ion channel was long thought to operate only in heart muscle, but recent work implied that it functions in other tissues. Now Alica Goldman, a neurologist and co-author of the paper, has discovered the first definitive evidence that the channel was working in mouse neurons. It was especially active in regions of the brain susceptible to seizures, the researchers report online this week in Science Translational Medicine. The team also monitored the mutant mice with EEG and ECG machines and determined that seizures often accompanied abnormal heart rhythm. "This is exciting because it provides the first molecular clue" that potassium ion channels underlie epilepsy and arrhythmia, says Jeffrey Noebels, a neurologist and lead author of the paper.

Noebels says misfiring by cells in the brain or heart might spur the release of stress hormones that cause the other organ to falter. Or aberrant electrical activity in one organ might spread to the other via nerves that connect them. But nailing down the exact connections will likely prove tricky. In the mice, the relationship between seizures and arrhythmia was erratic: One frequently happened without the other.

"The connection is still uncoupled in a sense," says Michael Ackerman, a pediatric cardiologist at the Mayo Clinic in Rochester, Minnesota. Ackerman has studied severe epilepsy and ion channels, and he says the paper is primarily a steppingstone. "The real proof is to go back from mouse to man," he says. That means determining how frequently mutations in the KCNQ gene cause epilepsy in humans.

Nevertheless, Noebels says the work already points to possible treatments for the most serious cases of epilepsy--the 10% of patients, most in their 20s and 30s, liable to die suddenly from seizures. Earlier research in humans implicated heart failure in many seizure deaths (Science, 4 July 2008, p. 31). Noebels hopes that treatments for faulty potassium channels in cardiac muscle, such as beta-blockers and pacemakers, can, if not prevent seizures, at least prevent deaths from seizures. "This is the first time we can say, well, if you have epilepsy, we should look at your heart, too," he says. "And you don't have to wait years to translate this into treatment."

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