Mayo Clinic and University of Iowa researchers have identified a new genetic mutation that may cause atrial fibrillation, the most common form of irregular heartbeat. The study's primary author, Denise Hodgson-Zingman, MD, assistant professor and electrophysiologist with UI Heart and Vascular Center at University of Iowa Hospitals and Clinics, talks about the study and its implications:

What is atrial fibrillation?

Atrial fibrillation is disorganized electrical activity in the top two chambers of the heart, which are called the atria. This results in the atria not beating regularly but instead, quivering or fibrillating and this has several other effects on the heart. Firstly, it results in blood not flowing smoothly through the atria that can cause a stroke and other complications due to the bottom chambers not beating regularly.

How many people are affected with an arrhythmia, or irregular heart beat?

There are many types of arrhythmias. They can be simply single extra beats that are really not dangerous at all and occur in many people, to very dangerous, life-threatening arrhythmia such as ventricular fibrillation which is irregular, disorganized beating of the lower chambers of the heart, which can cause sudden death. So, finding the exact number of people affected by all the different arrhythmias is difficult to estimate, but atrial fibrillation is the most common sustained heart rhythm disorder, and by the age of 40, the lifetime risk is 25 percent. So it's really a huge number of people that have atrial fibrillation and it's likely, because of our aging population, that those numbers will grow. So there's a little over two million people right now in the United States with atrial fibrillation and that's expected to double or quadruple in the next 35 years.

So do I understand that the older population is most likely to have atrial fibrillation?

You're absolutely right. This is an age-related degenerative process, so age is a major factor in the development of atrial fibrillation. But there are other medical conditions such as high blood pressure; valve disease; prior heart attacks; lung disease; or even congential heart problems like atrial septal defects; and heart failure, also, that can predispose to atrial fibrillation. And then there's some reversible causes like after having surgery, particularly in the chest cavity; having thyroid problems; or heavy consumption of alcohol that can cause transient atrial fibrillation. There are some cases that we don't know what the cause is. And occasionally we have cases that happen in young people and sometimes these are familial in the sense that they are inherited through the family, and we can tell by the pattern of the appearance in a family that there's inherited or genetic cause for atrial fibrillation. So this is a small proportion of the total number of people with atrial fibrillation, but does allow us to do studies like the one we're going to talk about.

Left untreated, what might happen to someone with atrial fibrillation?

There are several consequences of atrial fibrillation. It's not a fatal rhythm, it's a nuisance rhythm, but there are several serious complications that occur. The most dreaded is stroke. Because the top chambers of the heart do not beat regularly in atrial fibrillation (instead quivering), the blood doesn't flow smoothly through them. This can cause clots to form in the upper chambers that can then break off, go down to the lower chamber, and be pumped up to the brain, causing a stroke-so atrial fibrillation is a major cause of stroke. It's responsible for about 15 or 20 percent of all strokes. Atrial fibrillation can also cause the bottom chambers of the heart to beat very quickly, which makes them less efficient, and so people can suffer light headedness or shortness of breath; as well as fatigue from the bottom chambers going too fast. Also, one of the main functions of the atria is to prime the lower chambers of the heart, which are the main pumps, and without this priming action, a lot of people feel fatigue, as well. And finally, if the heart rates are too fast for too long, this can weaken the heart and cause heart failure.

What was the basis of your study?

What we wanted to do was look at patients who have a familial form of atrial fibrillation and we looked at a single family. The purpose was to try to find a new cause of atrial fibrillation by eliminating other confounding factors like other diseases such as hypertension and heart failure that we talked about. And looking at people that just had atrial fibrillation without other problems to see if we could identify what is the cause or what's setting the stage for development of atrial fibrillation in those people just to identify a new potential target or better understand the physiology behind atrial fibrillation.

Who participated in the study?

At the Mayo clinic there was a large family who consented to participate in the study and they had what was documented as an inherited form of atrial fibrillation. So they donated blood to be studied for genetic analysis and then, also, 560 unrelated people who did not have atrial fibrillation agreed to give blood to be studied for comparison.

What did the study indicate?

The study showed that in this family, the people who had atrial fibrillation had a mutation in the gene that encodes for atrial natriuretic peptide. This is a hormone that is secreted by the top chambers of the heart and circulates in the blood. It has hemodynamic and vascular effects; it regulates body water, and it regulates vascular tone, and has some effects on blood pressure. And so it is the first time that a hormone, circulating hormone, or any hormone really, has been implicated in this way in the edeology of atrial fibrillation. And it furthermore was shown that this hormone functionally is likely the cause of atrial fibrillation in these patients, as we tested in an animal model and found this abnormal peptide had electrical effects on the atria similar to what we would expect for normal, atrial natriuretic peptide, but in a much more potent way. This indicates that the mutation in the gene is the cause of atrial fibrillation in these patients, who really didn't have any other explanation for the atrial fibrillation. This really implicates an entirely new pathway that has not been investigated and that would open potential new pathways for treatment.

How is this genetic discovery different from other medical discoveries with regard to atrial fibrillation?

Other people have taken this approach, and using this approach, people have identified abnormalities in ion channels, which are channels in the membrane of the cells in the heart that allow things like potassium, sodium, and calcium to pass through. Several mutations have been discovered in those channels, and also in structural proteins in the heart, but no one has ever discovered a circulating hormone defect associated with atrial fibrillation. So this really offers an entirely new perspective on how we might go about testing for and treating atrial fibrillation.

Will this initial study serve a purpose in medicine today?

I think that the most immediate effect it will have is that it lays the groundwork for additional investigation into atrial natriuretic peptide. This peptide is something that can be tested in the blood and so I think some initial studies that people may find they're being asked to participate in would call for just testing the levels of atrial natriuretic peptide in the blood. Some similar studies have been done with this sort of testing in the past; but with this new information, I think there will be renewed interest in examining patients for their levels of atrial natriuretic peptide. And I think eventually what we'll do is when we better understand the entire sequence of events relating this hormone to atrial fibrillation, we'll be able to test new drugs; potentially drugs that block this peptide or change the potency of this peptide in some way to help prevent or treat atrial fibrillation.

What are the next steps in this research?

We need to really understand how this mutant peptide acts at the molecular level, so we need to find out how it binds the receptor; whether the increased levels of this that we see and the increase potency are related to receptor effects and to clearance of the hormone. That information then can be used to develop strategies to try to counteract these effects or enhance certain other effects that may balance out the negative effects of the atrial natriuretic peptides. So those are all things that need to happen in the future before we can really develop new therapies, but certainly this research will provide the groundwork for those sorts of studies.

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Denise Hodgson-Zingman, M.D.

UI Heart and Vascular Center