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Genetic Mutation Causes Cardiac Conduction Disease

March 13, 2001
Vanderbilt University Medical Center
Studies that started in an Amsterdam emergency room have yielded the first molecular insight into cardiac conduction disease -- a disorder that slows the heart rhythm, necessitating pacemaker implantation in millions worldwide.

Studies that started in an Amsterdam emergency room have yielded the first molecular insight into cardiac conduction disease -- a disorder that slows the heart rhythm, necessitating pacemaker implantation in millions worldwide.

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Cardiac conduction disease tends to afflict older patients, not young children like the three-year-old whose episodes of fainting during a feverish illness brought her family to the front lines of genetic research. The child and several other members of her family, it turns out, have a genetic mutation that causes cardiac conduction disease.

Scientists collaborating across the Atlantic describe the mutation and how it slows the cardiac rhythm in the February 22nd issue of Nature.

"Before this family came to medical attention, we had little insight into the molecular mechanisms that could potentially contribute to acquired conduction disease-the type that affects people as they age," said the report's senior author, Dr. Jeffrey R. Balser, associate professor of Anesthesiology and Pharmacology and holder of the James Tayloe Gwathmey Physician-Scientist Chair at Vanderbilt University. "We hope that this newly defined genetic mutation will serve as a model for understanding what's happening in aging hearts."

The child brought to the emergency room for fainting was suffering periods of a very slow heart rate-25 beats per minute instead of the normal 120 beats per minute for a child her age. The conduction disturbance persisted after the acute illness had ended, and her physicians ruled out other causes, including structural heart disease, viral infections, auto-immune disease, and thyroid dysfunction. The child required a pacemaker to regulate her heart rhythm.

Subsequent examination of family members revealed nearly identical findings in an older sister, who also required pacemaker implantation, and evidence of slowed conduction in three adults.

All of the affected family members have a genetic mutation that alters the activity of sodium channels, donut-like pores that control the passage of sodium ions across the heart cell membrane. Sodium channels are the primary proteins responsible for controlling the rate of electrical conduction through cardiac tissue, Balser said.

Sodium channel mutations are nothing new. But the mutations that have been described so far are linked to heart disorders characterized by tachyarrhythmias-irregular rapid heart rates-and sudden death. "How a mutation in the sodium channel could actually cause a slow heart rate was a complete mystery," Balser said.

The researchers used electrophysiological techniques to study the behavior of the mutant sodium channels in cultured cells. They discovered that the channels had multiple functional defects-some that let more sodium pass through the channel, some that allowed less through.

"In a sense, the mutation causes balanced deficits that mostly cancel each other out," Balser said. "So what you end up with is a very slight net decrease in sodium channel function. That slows conduction by about 10 to 15 percent, enough to slow the heart rate, but not enough to cause tachyarrhythmias and sudden death."

The findings open doors for research aimed at understanding much more common cardiac conduction disorders, including those seen with aging, Balser said.

"The heart is very sensitive to how its sodium channels work, and we suspect that aging may have subtle effects on sodium channels, not unlike the effects we see in this unusual family. We don't know that yet, but at least we have some insight now into how sodium channel defects can produce isolated conduction disturbances."

Balser and colleagues also made the surprising discovery that steroids inhibit the effect of the mutation. Steroids were used to treat the Dutch child before it was understood that she had a mutation-her physicians originally thought that inflammation of the heart might have been preventing normal conduction. Oddly, steroids improved her condition.

Likewise, when the investigators bathed the cultured mutant channels in steroids before studying their behavior, the functional defects disappeared.

"We theorize that steroids are inducing the production of a protein that interacts with the sodium channel and somehow cancels out the effects of the mutation," Balser said. "We'd really like to know if there is such a protein and what it is-if we knew that, it might be possible to provide that protein, instead of pacemakers, to patients with acquired conduction disease."

Collaborators on the Nature report include Vanderbilt scientists Hanno Tan and Prakash Viswanathan, and researchers in Amsterdam and Groningen, the Netherlands: Margreet Bink-Boelkens, Connie Bezzina, Gertie Beaufort-Krol, Peter van Tintelen, Maarten van den Berg, and Arthur Wilde. The studies were supported by the Interuniversity Cardiology Institute Netherlands, the Dutch Heart Foundation, and the National Institutes of Health.

Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.

Cite This Page:

Vanderbilt University Medical Center. "Genetic Mutation Causes Cardiac Conduction Disease." ScienceDaily. ScienceDaily, 13 March 2001. <www.sciencedaily.com/releases/2001/02/010226072358.htm>.
Vanderbilt University Medical Center. (2001, March 13). Genetic Mutation Causes Cardiac Conduction Disease. ScienceDaily. Retrieved March 31, 2015 from www.sciencedaily.com/releases/2001/02/010226072358.htm
Vanderbilt University Medical Center. "Genetic Mutation Causes Cardiac Conduction Disease." ScienceDaily. www.sciencedaily.com/releases/2001/02/010226072358.htm (accessed March 31, 2015).

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