A genetic variation, found predominantly in African Americans, protects some people with heart failure, enabling them to live longer than expected. That's the conclusion of a research team led by investigators at the University of Maryland School of Medicine in Baltimore and the Washington University School of Medicine in St. Louis.
The researchers found that the genetic variation acts just like beta-blockers, a class of drugs used to treat chronic heart failure. Study results will be available in the online version of Nature Medicine, on April 20, 2008.
In the study, the researchers found that African American heart failure patients with the genetic variation had a natural protection against death and the need for a heart transplant that is the same as the protection provided by beta-blocker therapy. Those patients who were given beta-blockers did not experience additional benefits from the medications because their own “genetic beta blockade” was already protecting them.
The researchers say their discovery adds to the accumulating evidence that genetic differences contribute to the way people respond to medications, and should encourage the use of genetic testing in clinical trials to identify people who can benefit from therapy tailored to their personal genetic makeup. “This is a significant development in our understanding of why some African American patients appear to not respond to beta-blockers in the same way as Caucasian patients,” says one of the study's co-authors, 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. “In this case, it seems that this genetic variation is a good thing, mimicking drugs that are frequently used to treat heart failure,” says Dr. Liggett.
Heart failure refers to the heart's inability to pump adequate amounts of blood through the body. Heart failure can be the result of hypertension or a heart attack. In some cases, called idiopathic cardiomyopathy, the cause is not identified. As heart failure progresses, adrenalin produces a “fight or flight” response to stimulate the heart into action by binding to receptors on heart cells called beta-adrenergic receptors. Over time, this attempt to enhance pumping in the diseased heart causes it to enlarge, change shape, and become even less effective as a pump.
In some patients, beta-blockers allow the heart to get some relief from the overactive pumping, develop a more normal cellular structure, and shrink in size. They do this by blocking or toning down the fight or flight response. Beta-blockers are a standard, highly effective therapy in some, but not all, patients with heart failure and ischemia, a cardiac blood flow disorder. But among African Americans, for unclear reasons, beta-blockers have had variable success.
To unravel this mystery, the researchers looked for human genetic variants in two types of genes associated with cardiac function, GRK2 and GRK5. These act as natural “brakes” to hold down overactive beta receptors. The researchers thought variants in these genes might modify the risk or outcome of heart failure, or alter the response to heart failure therapy. Nothing unusual came out of their search of the GRK2 gene.
However, in GRK5, they discovered a genetic variant. This was accomplished by taking genetic profiles of more than 2,000 volunteers in Cincinnati, Kansas City and Atlanta, including Americans of European descent and African Americans. Some of the volunteers had heart failure; others had ischemia; healthy volunteers made up a third group.