WASHINGTON (AP) - Scientists have discovered the molecular cause of a lethal type of irregular heartbeat and a drug that seems able to prevent it, a finding that might one day save hundreds of thousands of lives.
So far the experimental drug has been studied only in mice, but the Columbia University researchers hope to begin human testing next year.
Regardless of how that first attempt goes, the discovery is important because it provides a new target to treat not just irregular heartbeat but the huge problem of congestive heart failure, too.
"That's the exciting part about this work," said Dr. David Lathrop, who heads research into irregular heartbeat at the National Institutes of Health. "It's definitely a step forward."
At issue are ventricular arrhythmias, racing irregular beats of the heart's lower chambers. If it worsens, the heart quits beating and instead quivers, a condition called ventricular fibrillation that can kill within minutes. It claims about 340,000 U.S. lives annually.
Heart failure, where the heart muscle becomes progressively too weak to pump blood, is a major cause of ventricular arrhythmias. Heart failure afflicts about 4.6 million Americans and by itself is a relentless killer, but half of patients suffer ventricular arrhythmias, too.
Also, some patients inherit a form of exercise-induced ventricular arrhythmia.
In both types, sufferers have a leak in a tiny channel that regulates calcium levels inside their heart cells - and that leak triggers the deadly irregular heartbeat, discovered Dr. Andrew Marks, director of Columbia's Center for Molecular Cardiology.
The experimental drug, code-named JTV519, can literally plug the leak and prevent the irregular heartbeat, he reports in Thursday's edition of the journal Science.
Marks' laboratory bred mice to have the same leaky defect, and gave half the drug. Stressing them with exercise pushed all of the untreated mice into ventricular arrhythmias, and 89 percent died. But none of the mice given the drug could be stressed into the irregular heartbeat.
"There has to be some event at the molecular level that triggers the arrhythmia. We think we've discovered what that event is, and how to prevent it," Marks said.
An added bonus: The leak seems to worsen heart failure, too, so plugging it holds the promise to treat the overarching disease as well. In additional animal studies not yet published, Marks has found that fixing the leak improves overall heart function.
Today's heart-failure medications typically treat the symptoms, not the deadly disease's underlying cause, Marks explained. Many patients eventually need an implanted heart pump or a heart transplant - difficult and expensive options.
Nor are there good drugs to prevent ventricular arrhythmias; implanted defibrillators can shock the heart back into rhythm, if doctors realize someone's at risk in time to do the surgery.
Doctors have long known that calcium causes heart muscles to contract. The question was exactly how. Small calcium channels on the surface of heart cells play some role; indeed, calcium channel blockers are an old type of heart drug that limit the amount of calcium entering cells that way. They "have been real big disappointments," sometimes causing serious side effects, Marks said.
In contrast, Marks discovered a far bigger calcium channel that works inside heart cells - one he calls the key to controlling heart contractions.
Inside that "ryanodine-receptor channel" is a protein called calstabin2. Between heartbeats, it's supposed to keep the channel closed so calcium can't leak out.
But in heart failure and the inherited ventricular-arrhythmia syndrome, the calstabin2 doesn't do its job well enough. The resulting calcium leak worsens an already weakened heart, and destabilizes the heart cell's electrical activity so an arrhythmia can form.
The experimental new drug works by enhancing the natural protein's ability to close the channel - an entirely new approach of fixing a broken calcium channel instead of blocking it.
