A 19-year-old girl appearing on a live television show gotquite emotional, and suddenly dropped dead. A yearearlier, she had blacked out while running for a bus, butcame to. And as a toddler, she began having frequentfainting spells, which gradually grew less frequent.

This brief case history leads off a commentary in today'sNature titled "Ion channels lose the rhythm." It discussesan accompanying paper, "Molecular mechanism of aninherited cardiac arrythmia."

The young woman's electrocardiogram showed "aprolonged QT interval," molecular biophysicist PaulBennett, senior author of the Nature paper, explained toBioWorld Today.

Bennett, who heads a laboratory on ion channels atVanderbilt University in Nashville, Tenn., began: "Everytime your heart beats, 50 times a minute for example, anelectrical event occurs within that one beat that isapproximately 400 milliseconds in duration. During thatQT interval, all that happens in your heart of importance,like the pumping, occurs."

The electrical event that signals the heart to pump,Bennett said, reaches the cardiac cells by way of channelson the cell membrane surface, which permit sodium,potassium and calcium ions, among others, to trafficthrough the channel. The QT interval reflects the durationof electrical events that stimulate the pump.

Danger Of Arrhythmia

"The flow of those ions," Bennett continued, "are in adelicate inward-outward balance. Their imbalance createsprolongation of the QT interval, which sets into motion awhole series of events that we don't understand. If thechannels stay open too long, more ions can come in,which sets off an arrhythmia, which leads to short-termheart failure, and death, if not caught in time _ fiveminutes at the outside."

This congenital cardiac defect, known as the Romano-Ward syndrome, "is widespread and multifaceted,"Bennett observed, "but people hedge on its exactprevalence. Often individuals with the inherited formdon't make it into adulthood," he added. "What mayprecipitate their sudden death is not predictable."

Besides the familial form, he said, "a whole class ofpeople are susceptible to the syndrome through exposureto anti-arrhythmic drugs _ or other things we don'tknow about." This acquired form of LQT (long-QTinterval), Bennett noted, "affects about one percent ofpatients being treated on anti-arrhythmic drugs. Thisrepresents a fair number of people in our population,where cardiovascular deaths top all other causes ofdisease mortality."

Bennett pictures the sodium ion channel protein as "abagel or doughnut divided into four equal pieces." Headded, "The gene that encodes this protein resides onhuman chromosome 3, and encodes a product 2,016amino acids in length."

Mysterious Actions

While in an electrical state of negative membranepotential, the channel bars sodium ions from passingthrough its central pore into the cell. "Then," Bennettwent on, "when the electrical signal comes along and themembrane is depolarized, the pore opens up. Bymechanisms as yet unclear to us, it allows only sodiumions to pass. They flux in through the open pore at aphenomenal rate, some 10 million ions per second. Aftera few milliseconds the channel spontaneously inactivates,closes back and prevents that permeation. Then it repeatsitself over and over _ for life."

Except in individuals with a sodium ion channel long-QTmutation. "This," Bennett said, "occurs at a place in thechannel we think is the inactivation gate _ like a hingedlid closing over the pore and shutting down the channel.That's where mutation messes up inactivation."

"One form of hereditary long QT," the Nature paperreports, "has been linked to a mutation in the human heartvoltage-gated sodium-channel a-subunit (SCN5A) onchromosome 3p21)." That mutation deleted three of those2,016 amino acids, a lysine, a proline and a glutamine.

But, Bennett continued, "When we made that long-QTmutation, the mutated gene didn't behave as if that gatewere always defective. It seemed to go through periodicmodes, behaving normally most of the time."

"What are the implications of these molecular insights forclinical disease?" asks the author of the commentary,Michael Welsh, of the University of Iowa College ofMedicine at Iowa City. "First," he answers,"presymptomatic diagnosis should be possible, animportant consideration when the first manifestation ofdisease may be sudden death."

Next on Bennett's program is "to discover drugs thatwould suppress the prolonged opening of the sodiumchannel. Such a compound," he suggested, "would revertthose long-QT people with chromosome-3 mutations totheir normal state pharmacologically."

He suspects such treatment would have to be taken forlife, as insulin is in diabetes. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.