Mutation causes specific arrhythmia and sudden cardiac death

February 05, 2003

DURHAM, N.C. -- An international team led by researchers from Duke University Medical Center and the Howard Hughes Medical Institute (HHMI) have demonstrated a genetic basis for a fatal form of inherited cardiac arrhythmia that usually strikes young, seemingly healthy people.

The results of the study were published in the Feb. 6, 2003 issue of the journal Nature.

Basing their research on a French family with a form (Type 4) of inherited Long QT Syndrome (LQTS) and experiments in mice, the researchers found the mutation in a specific gene encoding ankyrin-B, a protein within heart muscle cells. Their discovery identifies what appears to be a novel mechanism for cardiac arrhythmia.

Normally, ankyrin-B acts as a biochemical symphony conductor, ensuring that microscopic pores in heart muscle cells known as ion channels open and close 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.

"We have found a brand new mechanism for cardiac arrhythmias based on the coordination of these different ion channels," said HHMI investigator and Duke cell biologist Vann Bennett, M.D., senior member of the research team. "It appears now that the arrhythmia arises, not due to some malfunction of the ion channels themselves, but a failure to ensure that multiple ion channels open at the right place and at the right time. Scientists have been looking for ion channel mutations, but they have not been able to find them."

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.

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. About one-third of patients with the disorder never experience symptoms, but those who do can experience loss of consciousness, abnormal heartbeats or sudden death.

LQTS is a dominant genetic disorder, meaning that each child of a parent with the disorder has a 50-50 chance of getting the disease.

In 1995, the researchers identified a large family in France with a preponderance of members with LQTS. A specific mutation, known as E1425G, was found to be associated with LQTS in 22 of 24 of the family members and with abnormal heart rhythms in 23 out of 24 members. The mutation was not present in more than 400 control samples.

The researchers then examined effects of this mutation on the important ion channels that regulate calcium levels in heart cells using their ankyrin-B mutant mouse model of LQTS.

"We found that two normal copies of the ankyrin-B gene are necessary for normal calcium signaling, and that the E1425G mutation leads to a loss of function," said Peter Mohler, Ph.D., HHMI post-doctoral fellow at Duke and first author of the paper. "So, ankyrin-B is the first identified protein implicated in a congenital LQTS that is not an ion channel."

The team performed further comparisons between humans with LQTS and mice with the E1425G mutation of ankyrin-B, and found striking similarities in cardiac performance, including reduced heart rate, a high degree of heart rate variability and other heart rate disturbances that could not be linked to electrolyte or structural defects of the hearts. They also found similar loss of function in ion channels other than calcium.

"Sudden death in humans with this mutation usually occurred after physical exertion or extreme emotional stress," Mohler said. "One of the members of the French family died suddenly at the age of 37 while running up a hill. So we wanted to see if this same effect would be present in the mouse models."

To simulate these circumstances, the researchers exercised the mice and then injected them with epinephrine, one of the so-called "fight-or-flight" hormones that stimulate the heart.

"Of the 14 mice with the mutation, two became unresponsive seconds after exercise, and eight died following exercise combined with the injection," Mohler said. "The effect was dramatic. None of the mice without the mutation showed any adverse effects from the exercise or the epinephrine."

Bennett believes that the insights gained in these experiments could also have important implications for disorders of other organs, especially those that like the heart, have excitable membranes responsible for proper organ function. These organs include the nervous system, the lining of the lungs and the kidneys, and beta cells in the pancreas that are responsible for release of insulin.
The research was supported by the National Institutes of Health, the Muscular Dystrophy Association, the Canadian Institutes of Health, the Institut National de la Sante et de la Recherche Medicale, and the Programme Hospitalier de Recherche Clinique.

Other members of the team are: Jean-Jacques Schott, Karine Haurogne, Florence Kyndt and Denis Escander, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moleculaires, Hotel-Dieu, France; Herve Le Marec, Hospital G&R Laennec, Nantes, France; Keith Dilly, Silvia Guatimosim, William H. duBell, Long-Sheng Song, Terry Rogers and W.J. Lederer, University of Maryland; and from Duke, Anthony Gramolini and Mervat Ali.

Duke University Medical Center

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