By David N. Leff
Young ladies in emotional distress don't swoon as often as they did in bygone times, when a whiff of smelling salts — aromatic spirits of ammonia — would snap them out of fainting spells.
When a patient with cardiovascular disease loses consciousness due to loss of blood to the brain, cardiologists call the episode a "syncope," not a swoon. And instead of smelling salts, they end the blackout with electric defibrillators, a shock treatment that restores normal heartbeat.
There is, however, a subset of cardiac patients who never make it to the emergency room; they drop dead in seconds from an unexplained, unpredicted heart event called idiopathic ventricular fibrillation (IVF).
Of the heart's four chambers, the ventricles are the two lower ones. They receive incoming blood from the two upper atrial chambers and pump it around the body. The right ventricle nourishes the lungs; the left one squeezes blood out to the rest of the body, including the brain.
Electric impulses signal the ventricles to contract and relax at intervals that define the normal heartbeat.
"What happens in ventricular fibrillation," explained clinical pediatric cardiologist and molecular geneticist Jeffrey Towbin, of Baylor College of Medicine, in Houston, "is that the heart muscle, instead of beating-relaxing, beating-relaxing, looks like a lot of snakes just writhing around without any synchrony. So blood doesn't get to the brain, and you have a fainting episode. If the heart spontaneously goes back to its normal beating rhythm, you wake up. If it doesn't, you die."
Towbin continued: "When someone drops dead at home, or on the basketball court, or someplace else, if the emergency medical resuscitation unit doesn't get to the patient within two minutes to administer defibrillator shock treatment, the victim's brain is fried, and if it lasts longer than that, he is fried."
Familial Form Holds IVF Key
Ventricular fibrillation takes the lives of some 300,000 Americans a year, of whom about 30,000 die suddenly of its idiopathic form. In a limited subset of these, the disease tends clearly to run in the family. But "because these number so few," Towbin pointed out, "and they die so suddenly, molecular genetic studies of IVF have not been done."
Until now, that is.
Tobin and molecular geneticist Quing Wang, also at Baylor, are co-senior authors of a paper in today's Nature, dated March 19, 1998, titled: "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation." Among the article's co-authors are investigators from Spain, Belgium, Italy, Germany and other U.S. centers. In search of the gene or genes responsible for the familial form of the disease, these collaborators pooled blood samples from their few high-risk IVF families.
Three mutations in the same candidate gene emerged from three of six families, plus two sporadic cases studied:
* In family K005, the index case, or proband, had a twin brother, who died of IVF at age 23.
* In K007, the three brothers died at 43, 46 and 55 years of age. The proband's father had two syncopes, at ages 20 and 34, before his fatal episode one year later.
* In K2823, the index case had four syncopal episodes. His father died suddenly from cardiac arrest at age 48, as did a cousin, at 27 years of age.
When blood samples from surviving family members reached Baylor, Towbin recounted, "we used a special approach to help us find out the underlying mechanisms that cause sudden cardiac death. Because it's hard to get blood from a dead person, we decided to immortalize the blood cells we received from those still living.
"So instead of just extracting the DNA and RNA from the white blood cells, we transformed those cells using Epstein-Barr virus into immortalized cell lines, capable of growing indefinitely on their own. We can take them out of deep-freeze at any time, regrow them and extract their DNA."
He made the point that "the IVF patient can die along the way, and we still have their cells. Many of those family members have in fact since died. Finding their genes during their lifetimes made this research possible."
Rather than opting for conventional linkage analysis, Tobin and his team built on the fact that "we knew there are certain ion-channel genes that produce certain types of proteins identified in cases where ventricular arrhythmias occur. One in particular is the 'long QT syndrome,' which we've been investigating for a number of years."
Wang, the Nature paper's co-senior author, had demonstrated in 1995 that mutations in one of these genes, SCN5A, occurred in families with long QT syndrome.
Tobin and his Baylor lab proceeded to test SCN5A in their reconstituted familial samples as a putative gene for IVF. Using a PCR-based screening technology known as single-strand conformation polymorphism, they identified three different mutations, one on each family's DNA. "They actually caused different changes in the level of activation — opening or closing of the channel itself — to allow the ions to pass through it."
Treatments Available For Families At Risk
To convey the impact of this discovery, Towbin said: "Suppose you have a family of a mother, a father and five children. Let's say the mother dies suddenly at age 40. She has a sister who does so at 45. One of the five kids has also died without warning.
"Well, it doesn't take a genius to figure out that there's a pattern here," Towbin went on, "nor to figure out that the other four children are at risk. So it would be nice to know in advance, before they drop dead, which ones carry the abnormal gene, so we can tell them they have IVF and treat them for it."
Towbin proposed two treatment modalities, one immediate, the other prospective.
"Probably the best approach currently," he suggested, "is putting in an indwelling, automatic defibrillator. The heart goes funky, and this device on top of it automatically goes off, and shocks the patient into a normal rhythm." He added, "These are already being provided to the familial families in our study."
Farther down the road, he concluded, "the other possibility is to develop special pharmacological therapy. So if we know this is a mutated channel, by using drugs that work directly on such channels, we may be able to correct the problem. Research is ongoing; such drugs are known." *