New Cardiac Arrhythmia Syndrome Identified

After discovering in 2003 a mutation in a specific gene in an extended French family for the arrhythmia, the researchers have identified four other similar mutations in different families worldwide, adding further evidence that they have indeed identified a new cardiac arrhythmia syndrome. The gene in question -- ankyrin-B -- encodes a protein that coordinates ion channels and transporters and thus regulates the flow of ions in and out of heart muscle cells, which in turn controls the beating of the heart.

The researchers believe that ankyrin-B mutations are more common than previously suspected, so they advocate that all family members of patients with sudden cardiac death undergo genetic testing. However, unlike other disorders with demonstrated genetic links but with no current treatments, the researchers said that beta blockers should be quite effective in controlling the irregular heartbeats.

The results of the study were published May 31, 2004, in the Proceedings of the National Academy of Sciences.

"When taken together with the results of our earlier studies, the current findings support a new paradigm for human disease based on the abnormal coordination of these related ion channels," said HHMI investigator and Duke cell biologist Vann Bennett, M.D., senior member of the research team. "We now have a new class of arrhythmias that had in the past been grouped with the Long QT Syndrome (LQTS) class of arrhythmias. We can now say that the new syndrome is completely separate and distinct."

The QT interval is a measurement taken by electrocardiogram that represents the period of time from electrical stimulation of the heart's pumping chambers to their recharging for the next heartbeat. In normal people, this interval ranges from 0.38 to 0.44 seconds. However, for people with LQTS, this period of recharging can be delayed up to 0.5 seconds, which put these patients at high risk for arrhythmias.

Patients with the ankyrin-B mutation typically have varying degrees of cardiac dysfunctions including increased risk of sudden death; however, prolonged QT intervals were not a consistent feature, indicating that this is a distinct arrhythmia, the researchers said.

In their latest studies, the researchers discovered four new mutations on a specific gene that encodes for ankyrin-B, a protein within heart muscle cells. Normally, ankyrin-B acts as a biochemical choreographer, ensuring that microscopic pores known as ion channels are correctly positioned in heart muscle cells so that they can work in a coordinated fashion. These channels allow such chemicals as calcium, potassium, sodium and chloride to pass in and out of the cell with each heartbeat, thereby regulating the electrical activity of the heart.

This constant back-and-forth electrical stimulation and recharging is controlled by different ions passing in and out of the cell, which alternately changes the cell's polarization. When this gene is mutated, the channels are not located properly in the cell, leading to abnormal heartbeats.

The team screened a group of 664 heart patients from the U.S. and Europe for mutations in the ankyrin-B gene and found eight patients with four new mutations, as well as the previously discovered mutation. In one instance, a family member had the mutation, but exhibited normal cardiac function. However, while the mother also had the mutation, three of patient's siblings died sudden deaths before the age of 25.

Ankyrin-B is not only found in muscle cells of the atria and ventricles, but also in nerve cells within the heart, leading researchers to believe that the gene could play important role in different aspects of heart function.

"Also, ankyrin-B is expressed by cells in different organ systems, including the insulin-producing cells of the pancreas, certain nervous system cells, the linings of the lungs and kidneys, and the retina," said Peter Mohler, Ph.D., HHMI post-doctoral fellow at Duke and first author of the paper. "For this reason, patients with the mutation in ankyrin-B may also exhibit problems other than, or in addition to, the documented heart effects."

For Bennett, the most recent discoveries open up "untapped and unexplored areas" for further research into mechanisms for organizing ion channels in cells.

"These findings provide a new way of looking at ion channels," he said. "In the past, researchers have been investigating mutations in the channels themselves, and not how they are coordinated and work together as a unit. If we can better understand the cellular mechanisms behind their actions, we should be able to develop promising new therapies for a variety of diseases."

The research was supported by the National Institutes of Health, the Leducq Foundation, Paris, and Johnson & Johnson, New Brunswick, N.J.

Other members of the team are: Igor Splawski, Leah Sharpe and Mark Keating of the HHMI and Harvard Medical School; Carlo Napolitano, Georgia Bottelli and Silvia Priori of University of Pavia, Italy; and Katherine Timothy of University of Utah, Salt Lake City.