Genetic Studies Reveal Complexities Of Heart Arrhythmias

NEW YORK, NY, July 26, 1998 -- Researchers at Columbia University have discovered how the mutation of a single nucleotide in a gene that encodes an ion channel in heart cells can cause a potentially fatal arrhythmia. The discovery also indicates that drugs now used to treat other forms of the disease, known as long-QT syndrome, are unlikely to work and may even exacerbate the problem.

"You have to know specifically what mutation you are targeting before determining the proper treatment," says Dr. Robert S. Kass, chairman of pharmacology at Columbia's College of Physicians & Surgeons. The findings, published in the July 27 issue of Circulation Research, highlight the fact that a single genetic disease may have several variations, each with its own mutation and mode of action. Treatment aimed at these variations, called gene-targeted pharmacology, promises to be a growing field in coming years.

In patients with long-QT syndrome, the muscle cells of the heart's ventricle take longer than normal to electrically reset themselves after contracting. People with this disorder live most of their lives with no symptoms and may not even realize they have it. But in times of stress, such as severe fright or extreme exercise, long-QT patients can develop fast, irregular heartbeats that cause fainting and even sudden death. An estimated 20,000 people in the United States have long-QT syndrome.

The inherited disease has been linked to mutations in five genes, four of which encode ion channels on the surface of heart muscle cells. The flow of positively charged sodium ions through one of these channels determines when and how long a cell contracts.

Dr. Kass led a team of researchers that studied a recently discovered mutant of the sodium-channel gene. The mutant gene, known as D1790G, has an adenine instead of the normal guanine at one location on the gene, which changes one of the channel's amino acids from aspartate to glycine. That mutation was engineered into isolated DNA encoding the channel, which was then transfected into cultured cells. The researchers then conducted experiments on these cells to determine precisely how the mutation altered the function of the ion channel.

The researchers found that the mutation caused the sodium channel to malfunction differently from other mutations studied. The previously studied long-QT mutations cause the sodium channels to repeatedly open and close when they should close tightly. The D1790G mutant opens and closes normally but only in a more electrically charged environment when the sodium channel building blocks are properly assembled.

It is not yet clear how this altered function contributes to long-QT syndrome. But it is clear that the medications normally used to treat the syndrome probably do not work for patients with the D1790G mutation. Those medications, the anesthetics lidocaine and mexiletine, have the same effect on sodium channels as does the D1790G mutation; they alter the channels' "voltage-dependence of inactivation gating." Initial results indicate that lidocaine and mexiletine do not work for patients with the D1790G mutation. It is not clear yet if they worsen the condition. "It is likely that the problem would be exacerbated by drugs used to treat the other mutations," says Dr. Kass.

Dr. Kass' discovery highlights the importance of knowing exactly what form of long-QT syndrome a patient has, then formulating a treatment based upon that form's genetic profile. He calls such treatment gene-targeted pharmacology. "Genetic screening of patients is very important," says Dr. Kass.

Although long-QT syndrome is relatively rare, Dr. Kass says the lessons it provides about the value of gene-targeted pharmacology will apply to many genetic diseases in the future. Rarely do all people suffering from a single genetic disease have exactly the same mutation in their DNA. Different mutations produce slightly different disease characteristics requiring different treatments. As the Human Genome Project and other genomic research reveal more and more about the genetics of disease, these variations will become more evident. That knowledge will offer more opportunities for gene-targeted pharmacology to provide effective treatments for genetic diseases.



Circulation Research, DNA, Human Genome Project, QT