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Can life-threatening arrhythmias associated with heart failure be prevented with a pill? CUMC cardiologists think they may have created such a drug, which could help the 5 million Americans who suffer from heart failure and decrease the hundreds of thousands of deaths attributable to heart failure-induced arrhythmias each year.

A recent test of the drug in mice, the results of which were published in the April 9 issue of Science, showed the drug completely prevents sudden death from arrhythmia in mice that have the same heart defect as people with heart failure.

"The drug will be an incredible advance if it works in patients," says Dr. Andrew Marks, chairman of physiology and cellular biophysics, director of the Center for Molecular Cardiology at CUMC, and leader of the new study. "It represents the beginning of an era when drugs will directly fix the molecular defects in heart failure. While our drug is one of the first molecular-based therapies for heart failure and arrhythmias, it won't be the last."

Heart failure is not the same as a heart attack; rather, it is a weakening over years of the heart's ability to pump blood. About 550,000 new cases are diagnosed each year; heart failure is the only heart condition still on the rise in the United States.

Few choices for heart failure

About half of the millions of patients with heart failure in the United States will die from a type of arrhythmia that produces a fast and erratic beating of the heart. But medications that prevent arrhythmia are so toxic that most have been removed from the market. Other options, defibrillators and heart transplants, are highly invasive or cost hundreds of thousands of dollars.

In the new study, the experimental drug was tested in mice. The mice had the same molecular defect as people with heart failure and some otherwise healthy people who die suddenly during exercise.

The defect causes a tiny channel in heart muscle to leak calcium ions into heart cells. The leak can trigger a fatal arrhythmia at any time in heart failure patients or during exercise in people with an inherited defect in the channel.

All 10 mice that received the drug thrived and never developed an arrhythmia, while eight out of nine untreated mice became arrhythmic and died.

The new drug, developed by Dr. Marks based on 15 years of research, prevents arrhythmia and sudden death by patching the leak in the heart's calcium channels. Work in Dr. Marks, lab had elucidated how the channel works to make the heart beat, and in the past few years, his lab has revealed the channel's connection to heart failure and fatal arrhythmia.

The compound is similar to a drug designed by a Japanese company and tested in people with a different type of arrhythmia. Although the drug failed to prevent those arrhythmias, it did appear to be safe.

Dr. Marks and Dr. Donald Landry, professor of medicine, have since modified the molecule to produce a drug 200 times more effective than the one tested in the Science study. Dr. Marks hopes to get the new compound into clinical trials in the next two years.

The experimental drug also has great potential to prevent the relentless deterioration of the heart during heart failure, because the same leak that can trigger an arrhythmia also contributes to the heart's worsening function. The heart spirals into decline because the constant drip of calcium through the channel leaves little in store when heart muscles need the calcium to contract. With little calcium, the heart can only pump weakly. The body tries to compensate but only succeeds in making the channel even leakier and the heart less and less effective.

Beta blockers, which have been shown in recent years to improve the survival of heart failure patients, also help stop the leak. However, beta blockers are nonspecific and they have side effects that limit their use in some patients.

"By fixing the leak, you could potentially slow the progression of heart failure and allow patients to live their lives more normally, not in and out of hospitals," Dr. Marks says. "Our idea is to take a pill instead of spending hundreds of thousands of dollars on invasive devices and heart transplants."

The research was supported by the NHLBI and a Glorney-Raisbeck Fellowship. Dr. Marks is a Doris Duke Charitable Foundation Distinguished Clinical Investigator.

–Susan Conova