July 10, 2008
UI helps identify gene mutation related to atrial fibrillation
Mayo Clinic and University of Iowa researchers have identified a new mechanism of atrial fibrillation, the most common form of cardiac arrhythmia (irregular heartbeat).
The researchers discovered a mutation in a gene that encodes a hormone originating in the atria of the heart, and they established the mutation as causative of atrial fibrillation. This discovery opens a new avenue to pursue for possible treatments.
The study was based on the analysis of genetic information from one Caucasian family and other control subjects, and investigations in animal models. The study results will appear online July 10 at the New England Journal of Medicine Web site.
"While the family members with atrial fibrillation have a rare mutation, the study findings provide insight into pathways that may be applicable to people in the general population with atrial fibrillation," said the study's primary author Denice Hodgson-Zingman, M.D., (photo, left) assistant professor of internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine.
"Atrial fibrillation is a significant public health concern. Nearly one in four people age 75 and older has the condition, and it is a major cause of stroke," said Hodgson-Zingman, who also is an electrophysiologist with UI Heart and Vascular Care.
The study indicates that disturbances in a pathway involving atrial natriuretic peptide (ANP) promotes atrial fibrillation. ANP is a hormone that regulates body water, sodium and certain vascular effects.
"Usually inherited arrhythmias are associated with mutations in heart structural proteins or ion channels," Hodgson-Zingman said. "It is intriguing that we identified a circulating hormone as a cause of atrial fibrillation because this gives us a potential new target for developing treatments."
The senior author of the study, Timothy Olson, M.D., associate professor of medicine and pediatrics at Mayo Clinic, led a team of investigators that gathered and analyzed genetic data from the affected and unaffected family members and control subjects. They found that the 11 family members with atrial fibrillation had a shared mutation in the gene that encodes for ANP. The mutation was not found in family members without atrial fibrillation or in unrelated patients without the condition.
The team also determined that in patients with the mutation, the blood concentration of the abnormal peptide is much higher than that of normal ANP, which is present at typical levels (because the mutation is in only one of the two copies of the gene, the persons with the mutation also make normal ANP).
UI researchers Hodgson-Zingman and co-author Leonid Zingman, M.D., (photo, right) assistant professor of internal medicine at the UI Carver College of Medicine, used animal models to establish that mutated ANP causes changes in heart electrical function expected to promote atrial fibrillation, thus providing crucial evidence that the mutated ANP is not neutral or an incidental finding.
The study also suggests the mutant peptide appears in the plasma in high levels, either because it is not broken down or more of it is generated than normal. "It is more likely that the peptide is not broken down as quickly, but additional research is needed. It also is possible that when concentrations are abnormally elevated for long periods of time, they could have toxic effects on the heart," Hodgson-Zingman said.
The UI results also suggest that mutant ANP may be more potent in its cellular effects than non-mutant ANP.
"The potency issue is important because it suggests changes to the peptide could be used for therapeutic purposes. However, more studies would be needed to determine how the peptide binds to receptors and affects downstream mechanisms," Hodgson-Zingman said.
Atrial fibrillation occurs when rapid, irregular electrical activity occurs in the top two chambers of the heart (the atria). As a result, the chambers do not beat as they normally should but instead quiver.
"The chaotic activity results in less efficient blood flow and can lead to clot formation with consequent stroke, and to rapid, irregular beating in the lower chambers of the heart, causing further problems," Hodgson-Zingman said.
Currently, there is no cure for atrial fibrillation. Treatment for people with the condition focuses on preventing stroke through the use of aspirin or other blood thinners, and symptom control through medications or invasive procedures.
The study was supported by a grant from the National Institutes of Health. In addition, Olson received a Mayo Foundation award.
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