Heart drug riddle solved

Beta blockers' ability to combat chronic failure linked to genetics


THE EFFECTIVENESS OF BETA BLOCKERS — Researchers at the University of Maryland School of Medicine say they have solved a mystery that has intrigued cardiologists for years: why one of the most commonly prescribed heart medications doesn't always work.

The effectiveness of beta blockers - a class of drugs given to many of the estimated 5 million patients with chronic heart failure - depends on the genetic makeup of receptors in the heart, said Dr. Stephen B. Liggett, head of the school's cardiopulmonary genomics program and lead author of the beta blockers study.

The findings, published today in Proceedings of the National Academy of Sciences, could help determine the course of treatment for those with chronic heart failure, sometimes called congestive heart failure. A genetic test could be approved by the Food and Drug Administration in the next year or two, the researchers say.

"I think this is really exciting news for people who treat heart patients, both cardiologists and internists," said Dr. Roger S. Blumenthal, a cardiologist who is director of the Johns Hopkins Ciccarone Preventive Cardiology Center and was not involved in the study.

The study focused on patients diagnosed with heart failure, and the researchers say they are unsure if the benefits would apply to patients who take beta blockers to lower blood pressure or prevent heart attacks. Separate studies would have to be conducted to determine that, they say.

"This may be something that's particular to heart failure patients," said Dr. Michael Bristow, a cardiologist at the University of Colorado School of Medicine and a co-author.

Bristow and other experts say the findings also represent a step toward a goal that has been the subject of medical research for years - tailoring therapies and medications based on individual genetic differences. Promising results for genetically tailored therapies have also been discovered by researchers probing childhood leukemia, asthma, breast cancer and anti-coagulant drugs, Liggett said.

Heart failure usually develops when the heart is unable to pump enough blood to supply the body. The heart tries to compensate by growing larger and pumping faster.

Someone is predisposed to heart failure if they have had a heart attack or have high blood pressure, abnormal heart valves or diabetes. Because the changes occur gradually, symptoms are often missed until the heart can't keep up with the body's requirements and a person begins to feel fatigued and have trouble breathing.

But heart failure can kill quickly. One in five chronic heart failure patients is dead within a year of being diagnosed and less than half live for more than five years, researchers say.

"You have a very narrow window before the progression of the disease gets out of hand," Liggett said.

Beta blockers are one of the most commonly prescribed medications for heart failure, because they are believed to slow down the heart and prevent an irregular heartbeat by blocking the receptors that normally respond to adrenalin. But they don't work in one of four patients, and how well they work in others can vary, said Dr. Mandeep Mehra, chief of cardiology at the University of Maryland School of Medicine, who was not involved in the study. Moreover, they have side effects that include depression, fatigue and asthma-related lung problems.

"It's important to know what medication is working and what isn't," Mehra said.

In the study, the researchers compared the success rate of an experimental beta blocker given to patients with genetic variations in a type of heart receptor that researchers believe is targeted by beta blockers.

Liggett had discovered in 1999 that people have two variants in the heart's beta one receptors: one known as arginine and another known as glycine. In the study being published today, the researchers found that the patients with two copies of the arginine variant lived on average 38 percent longer than patients with the glycine variant. Patients with the glycine variant didn't respond to the beta blocker.

The study is a follow-up to work completed in 2001, when researchers at the University of Colorado School of Medicine conducted a clinical trial to test the effectiveness of bucindolol, a beta blocker developed as a heart medication. They tracked bucindolol's effectiveness at treating 1,044 heart failure patients for four years and initially concluded that the medication was of no benefit.

But it was only by analyzing each patient's DNA profile that the genetic link became apparent, Liggett said.

"Our idea was always that there was a genetic reason for why these beta blockers work in some patients but not others," Liggett said.

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