Genetic Variation Predicts Response to Heart Failure Medication

Researchers at the University of Maryland School of Medicine in Baltimore and the University of Colorado School of Medicine in Denver have identified a common genetic variation that could help determine whether a person with heart failure would benefit from beta-blockers, a class of drugs used to treat chronic heart failure. The findings are significant because it often takes several months to determine if a specific beta blocker is working for a patient. Time is of the essence because one in five patients with heart failure will die within a year of diagnosis. The findings are published online this week in the Proceedings of the National Academy of Sciences.

In a study that compared an investigational beta-blocker to a placebo (or sugar pill), researchers found a 38 percent reduction in the death rate among patients who took the beta-blocker and who also had two copies of a genetic variant called arginine (Arg-389). In addition, these patients had a 34 percent reduction in another benchmark, the combined number of hospitalizations and deaths. People with another genetic variant, glycine (Gly-389), had no response to the drug compared to the placebo.

"For the first time, we have a genetic test that will help guide us to the best treatment for individual patients with heart failure and provide what has been called personal medicine," says the study's principal investigator, Stephen B. Liggett, M.D., professor of medicine and physiology at the University of Maryland School of Medicine and director of its cardiopulmonary genomics program. "This personalized therapy, based on genes, gives us an opportunity to tailor therapy in a way that we really were never able to do before," says Dr. Liggett.

The genetic variance occurs in the beta-1 adrenergic receptor, which is the target for beta-blockers. People either have the Arg variant or the Gly variant. Dr. Liggett says the type of variant does not predispose a person to develop heart failure.

Beta-blockers reduce demand on the heart, slow the heart rate and prevent irregular heartbeat. They block receptors in the heart that normally respond to adrenalin and cause the heart to pump stronger. In heart failure, the heart's impaired pumping function causes adrenalin to make the heart work harder. Beta-blockers allow the heart to get some relief from the overactive pumping, develop a normal cellular structure and shrink in size.

Despite their usefulness, beta-blockers and other heart failure drugs present a treatment challenge, because their effect on a given patient is somewhat unpredictable. "It has been difficult to explain the variability of response to treatment, even among patients with similar ages and other characteristics. This is especially the case with beta-blockers, one of the cornerstones in the treatment of heart failure," says Michael Bristow, M.D., Ph.D., a cardiologist at the University of Colorado School of Medicine and one of the study's authors. "We hypothesized that the variability in response to beta-blockers was due to important functional genetic variation in the beta-1 receptor, and this indeed appears to be the case."