Researchers Link Gene Defects to the Course of a Deadly Form of Heart Disease

Results in New England Journal of Medicine October 1st

September 30, 1998

Researchers have linked defects in three specific genes directly to the progress of a form of heart disease, coupling for the first time the presence of defective genes to the course that patients can expect the disease to take throughout their lifetime. The work on Long QT Syndrome, a heart-rhythm disorder that afflicts an estimated 25,000 Americans and kills at least 3,000 of them without warning each year, is reported in the October 1 issue of the New England Journal of Medicine by researchers at the University of Rochester Medical Center.

The findings mean patients with Long QT Syndrome will soon be able to learn whether they carry a defective gene that will cause them simple fainting spells, or forms of heart-rhythm disorders that can result in sudden death. Further, the study serves as a harbinger of the future of medicine, when doctors will use the knowledge of a person’s genetic makeup to specify a treatment.

"Eventually, every discovered gene should be related to improving the care of patients, because that’s what medicine is all about," says Arthur Moss, M.D., a co-author of the study and one of the world’s leading experts on Long QT Syndrome. "It’s one thing to figure out which genes are related to different disorders, but in this study abnormal genes are being related directly to the different courses the disease can take. This approach of linking a defective gene to a clinical outcome is the major direction medicine will take in the next century."

Long QT Syndrome is a genetic disorder that can stop its victims’ hearts when they become excited. A telephone ring in the middle of the night or an exciting game of bowling can be fatal. Living with this disease means thinking twice about jumping into a swimming pool, working out, or playing sports without a "buddy" who can call 911 if trouble strikes.

Though the syndrome appears to be a single disease, it’s actually the result of one of three possible defective genes that express themselves in similar ways. To properly attribute each "version" of the syndrome to the responsible defective gene, researchers Moss and Wojciech Zareba M.D., Ph.D., at the University of Rochester, enrolled 1,378 patients with the disease at four medical centers around the world, and carefully matched each gene to each person’s medical history.

The team found a direct correlation: The progress of the disease can be related directly to which of the three genes is defective, making Long QT Syndrome the first heart disease with a course that can be predicted from a patient’s genes. The team found that two of the damaged genes are responsible for heart defects that are more likely to lead to recurrent fainting spells, while the third damaged gene is responsible for a defect that is far more likely to be fatal. Knowing which gene is defective tells doctors what course the disease will take, and it enables them to treat each patient far more effectively.

A blood test is currently being developed which will be able to tell patients with Long QT Syndrome which of the three genes is causing their disease. Moss anticipates that the blood test will be available in doctors’ offices within three to six months. Armed with the results of this test, some patients will be able to rest easier knowing that their frequent fainting episodes are not likely to be fatal. For patients who are found to have the more serious genetic defect, physicians may emphasize the importance of taking their medications and having a plan of action in case of emergency. But the future holds even greater promise for these patients: Moss and Zareba have already begun to apply their research findings in an effort to develop gene-specific therapies for Long QT Syndrome - including one that is expected to be much more effective in treating the often-fatal form of the disease.

Moss became interested in Long QT Syndrome when, 30 years ago, Helen Pontera, a 39-year-old woman from upstate New York, bowled a strike - and immediately fainted. Though she appeared healthy when she awoke, she experienced four more similar episodes over the following year: twice more while bowling, and once while dancing with a young man. "Later I had to explain that I wasn’t swooning over him," she says. It wasn’t until she lost consciousness in the hospital and had to be resuscitated with a defibrillator that doctors knew something was seriously wrong with her heart. She was admitted to the University of Rochester Medical Center where Moss found a strangely long interval between the Q and T waves on her electrocardiogram tracing.

The Q-wave on an electrocardiogram denotes when the cells that make up the heart muscle begin to "electrically recharge" after each pump, and the T-wave signifies the end of the recharging cycle, when the heart is ready to pump again. A long Q-T interval indicates that the heart muscle is having difficulty recharging. The problem arises from defects in the tiny channels that allow electrically charged ions to flow in and out of the cells. This flow of ions is crucial to the proper contraction of the heart muscle.

When the gene that carries the blueprint for the design of these channels is defective, the channels become defective, and the ions don’t flow smoothly. Not only does this result in a longer "recharge" interval, but the channels may malfunction entirely in times of stress – often stopping the heart completely. A scare behind the wheel, a slamming door, even a game of bowling - all can be fatal.

"The investigation into Long QT Syndrome is one of the National Institutes of Health’s highest priorities," says Moss, "because many doctors see it as the ‘Rosetta stone’ of cardiac diseases. Understanding the heart when one disease makes it malfunction sheds new light on how other diseases affect the heart. This study may one day help in the treatment of other forms of heart-rhythm disorders, like fibrillation, which kill an estimated 400,000 Americans each year."

Physicians already have genetic tests for hundreds of disorders at their disposal, but too often the test simply tells the patient whether he or she has a specific disease, not how to treat it. The results of this study show that cardiologists can use genetic studies as a road map for treating Long QT patients, Moss says. "Our hope is that the vast wealth of genetic information being mined through the Human Genome Project can be used in a similar fashion."

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