Iowa City, IA - US researchers have found that a mutation in the gene that encodes atrial natriuretic peptide (ANP) appears to be responsible for hereditary atrial fibrillation (AF) [1]. The discovery is unexpected "and is the first time that a hormone has been found to be associated with AF," lead author Dr Denise Hodgson-Zingman (University of Iowa, Iowa City) told heartwire. The findings are reported in the July 10, 2008 issue of the New England Journal of Medicine.

The gene for ANP was pinpointed during a linkage analysis and candidate gene study of one extended family in which 11 members had familial AF, carried out by Dr Timothy Olson (Mayo Clinic, Rochester, MN) and colleagues. The mutant peptide produced was then perfused into isolated animal hearts by Hodgson-Zingman and her team in Iowa, and it had electrophysiological actions on the atria that predispose to AF. "So that was kind of functional evidence that this was not a neutral peptide or a coincidental finding," she said.

There are important implications to this discovery, she adds. "Obviously, we need to do further work to see how this mutant peptide is causing AF, but this offers a new potential target for drug therapy for AF."

The researchers explain that they mapped an AF locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding ANP. Affected members had the mutation, but those who did not have AF did not. Furthermore, the family members with AF had the mutated protein circulating in their blood in much higher concentrations than the normal peptide.

Hodgson-Zingman explained that all prior gene mutations associated with AF have been in sodium or potassium channels or in structural proteins.

"Although we need to do further studies, and this is purely speculative, we suspect that this mutant ANP is probably working through the regular pathways of ANP, but it's not been broken down as easily because there are high levels of it. This may be causing toxic injury to the heart in the long term and in the short term having electrophysiological effects," she says.

"If we can understand better how this mutant peptide is causing AF, we may be able to make, for instance, a blocker of this peptide that doesn't have the same side-effect profile as an ion-channel blocker. That has really been the limitation in treating AF—most of the drugs we have are not specific for the atria, they affect the ventricles as well, and so we have some proarrhythmia."

She cautioned, however, that this was obviously a study performed in a family with familial AF and so it will be important to establish the significance of the findings in sporadic AF.

This offers a really novel target that will hopefully open up some new pathways for new treatments for AF.

"But we are hopeful that this means that normal ANP or its receptor might be manipulated in some way in people with more sporadic forms of AF. This offers a really novel target that will hopefully open up some new pathways for new treatments for AF. It's a totally new direction that we can attack and hopefully provide something beneficial for patients."

Olson said the research also offers a potential window of opportunity for early diagnosis of AF, before the development of clinically overt disease. His team is continuing to work on the genetics of familial AF and has recruited nearly 50 families with the condition.