Science Editor

The sinoatrial node is "part of the heart, but a very specialized part of the heart," Mark Anderson told BioWorld Today. The cells that make up the pacemaker are different from normal cells, he explained. They are "more effective at beating on their own, but they don't have much mechanical function," or as much strength to contract as regular heart muscle cells. "They just kind of quiver."

But that quivering, he explained, is critical to heart function; it is how "each normal heartbeat is initiated." So when things go wrong with node cells, slow and irregular heartbeats can result, necessitating an artificial pacemaker to take the place of the biological one.

Anderson is chair of the Department of Internal Medicine at the University of Iowa's Carver College of Medicine, and the senior author of a paper that described the molecular underpinnings of such dysfunction. His team's work was published in the July 25, 2011, of the Journal of Clinical Investigation.

Sinoatrial node dysfunction often occurs together with other heart problems, and so Anderson and his team suspected that there might be common underlying molecular mechanisms that different cardiac problems share. Fluctuating levels of calcium across different cell compartments are a critical factor in heartbeats, and one particular enzyme, calcium calmodulin kinase (Cam kinase II) is "emerging as a controller" of cardiac cell function, prompting Anderson and his team to look at whether oxidized Cam kinase II played a role in sinoatrial node dysfunction.

Cam kinase II is normally activated by calcium, but if one particular amino acid on the kinase is oxidized, it traps Cam kinase II in an active position.

They first looked at the levels of oxidized Cam kinase II in patients with various cardiac problems, and found that "patients that needed a pacemaker had much more of this oxidized Cam kinase II in regions near the pacemaker [cells]," Anderson said. In a dog model of sinus node dysfunction, too, the team saw the same "signature of too much oxidized Cam kinase II near the pacemaker region."

To test whether shutting down hyperactive Cam kinase II would have an effect on sinoatrial node dysfunction, first author Paari Swaminathan developed different mouse models and techniques to specifically inhibit oxidized Cam kinase II in the sinoatrial node.

In a nutshell, Anderson said, those experiments showed that oxidized and thus hyperactive Cam kinase II "causes cell death in heart muscles."

That cell death is not unique to the cells of the sinoatrial node, but because there are comparatively few of them around to begin with, such cell death is more keenly felt. Even though some of the node cells still worked with high levels of oxidized Cam kinase II, collectively, "there just weren't enough of them to electrically control the rest of the heart," which could result in an erratic heartbeat.

The most important advance of the paper, Anderson said, is "the discovery of some clear molecular machinery" that underlies sinoatrial node dysfunction. Previously, despite their importance in keeping the heart going reliably, very little was known about how things went wrong with the node, if and when they did.

That machinery could ultimately be targeted therapeutically. Currently, Anderson and his team are looking at the exact places in the cell where Cam kinase's effects play out. They are also looking at developing pharmacological inhibitors, but Anderson noted that Cam kinase II is "widely expressed," and so it is necessary to "grapple with the idea that there might be unintended consequences" of inhibiting it pharmacologically.

Another possibility is to attack the problem with a mix of surgery and genetic techniques.

"We know who is at risk for sinus node failure," Anderson said. One possibility would be to use something analogous to gene painting if and when patients who are at risk for sinus node failure, but do not yet have a pacemaker, need to have heart surgery for other reasons.

Such an approach, if successful, would "not eliminate pacemakers, but might reduce the number of people that eventually go on to need to have them."

Pacemakers, he said, are "much better than what we had before; in fact, "I spent many years putting them in."

But "they are not perfect" – they can fail, they can cause infections, and even when they work well, they need to be replaced every decade.

For now, however, such practical applications are a ways off.

"There are many steps that would have to occur to see whether that's a viable therapy in people," he said.