The discovery, another step toward personalized medicine, may explain why beta-blockers do not work for all patients
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 (www.nature.com), 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.
To deepen their understanding of the genetic variation, the researchers created cell lines and developed genetically altered mice to predict how the gene would function in humans. They discovered that the genetic variant acts in a way that is identical to beta-blocker drugs, reducing the impact of adrenalin that forces the heart to work harder. In an experimental model, the variant protected the mice from developing heart failure after exposure to a substance similar to adrenaline.
Armed with this information, they launched a prospective study of 375 African Americans with heart failure at the University of Cincinnati and followed them for an average of two-and-a-half years. Some were on one of the two commonly used beta-blockers in the United States (carvedilol or metoprolol); others were not on beta-blockers. While the presence of the variant did not prevent the onset of heart failure, those with the variant who had heart failure were just as protected as those without the variant who were on beta-blockers.
The researchers say this particular genetic variant occurred in about 40 percent of African Americans they studied. The variant also occurs in about two percent of Caucasians. While it is likely to be a factor in those patients as well, a much larger study would be required to verify this, because the variant is so uncommon.
"For several years, a controversy has existed in the cardiovascular field because of conflicting reports about whether beta-blockers helped African-American patients," says co-author Gerald W. Dorn II, M.D., professor of medicine, associate chairman for translational research and director of the Center for Pharmacogenomics at Washington University. "By mimicking the effect of beta-blockers, the genetic variant makes it appear as if beta blockers aren't effective in these patients."
According to Dr. Liggett, the discovery of this variant is another milestone on the road to personalized medicine. "In heart failure treatment, there is still a lot of 'one drug fits all' thinking. This variant is one of what may be many genetic variants that can be used like a 'scorecard' to guide treatment in a much more personalized way," says Dr. Liggett. He adds that the University of Maryland School of Medicine has multiple research studies underway to further identify by genetic means which patients should be treated with which drugs.
More than five million Americans have heart failure, with 550,000 new cases diagnosed each year. Fewer than 50 percent of patients live past five years after their initial diagnosis and fewer than 25 percent are alive at 10 years, according to the Heart Failure Society of America.
Researchers from the University of Cincinnati College of Medicine and the University of Michigan also participated in the study. A grant from the National Heart, Lung, and Blood Institute supported this research.
Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SLR, Dorn II GW. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nature Medicine April 20, 2008 advance online publishing).