Genes influence how heart failure patients respond to drugs

Genes dictate the color of our hair and eyes. They factor into whether we get cancer or heart disease. And, scientists increasingly recognize, they also ensure some patients will benefit from a prescription drug, while others develop adverse reactions or simply fail to respond at all.

Now University of Florida researchers have discovered that patients with heart failure can harbor genetic variations that determine whether they will tolerate the common heart drugs known as beta-blockers. In a separate study, they also determined certain genes influence whether beta-blockers successfully restore the heart to a more normal shape and size in these patients. The findings, published recently in the journal Clinical Pharmacology and Therapeutics and the journal Pharmacogenetics and Genomics, highlight the need to individualize therapy, as opposed to treating all people with a certain disease generally the same, said the studies' principal investigator Julie Johnson, Pharm.D., director of the UF Center for Pharmacogenomics.

Although diet, age, health status and the environment also shape how people respond to medications, personalizing drugs based on genetic makeup instead of taking a trial-and-error approach could lead to safer, more effective treatments, said Johnson, also a professor at UF's colleges of Pharmacy and Medicine and chairwoman of the department of pharmacy practice. Because of hereditary factors, some patients break down drugs more slowly, so the amount of a certain medication may soar to toxic levels in the body. Others metabolize drugs quickly, and never accumulate enough in the bloodstream to ease what ails them.

"In the past five to 10 years, there's really been an increased interest in understanding the role of genetics in determining how people respond to drugs," Johnson said. "The reason for that is that we know that in a group of individuals, a certain portion will have side effects, or toxicity from a drug, a certain portion will derive the benefits we want, and some won't derive any benefit. The long-term goal is to try to be able to determine that before we actually have to give them the drug."

A clearer understanding of who would benefit from beta-blocker therapy also would ensure more patients would be helped, Johnson said, citing a serious international problem with both underuse and underdosing of the drugs.

In the past five years, beta-blockers have become a standard part of the treatment for heart failure. Patients with the disorder have enlarged hearts that lose the normal heart shape and become rounder and somewhat baggy. Beta-blockers help restore the heart to a more typical shape and size and, in doing so, improve heart function. The drugs also have been shown to prolong life and reduce the rate of hospitalization for heart failure symptoms.

But patients who start taking beta-blockers must begin at very low doses that are slowly increased over a series of months. Some patients tolerate them well; others have difficulty and suffer adverse reactions such as a worsening of their heart failure symptoms. Those patients, who may experience shortness of breath, ankle swelling or fluid retention in the lungs, fatigue and reduced ability to tolerate exercise, require even more time to adjust to increasing doses, and some must switch to other medicines.

"At the moment, the consensus guidelines for treatment of heart failure are that basically everyone should get this drug," Johnson said. "I'm certainly not sitting here saying we should change those consensus guidelines, which come about because of large clinical trials and because of benefits that are shown in large clinical trials. But we know that, at an individual level, not everybody benefits from any given therapy."

So UF researchers set out to determine whether variations in an individual's genetic code might influence how well a patient tolerates beta-blockers once therapy is begun. They took blood samples from 61 heart failure patients, focusing on a particular gene called the beta-one adrenergic receptor gene, which makes a protein that beta-blockers bind to.

Differences within that gene among individuals helped predict those who were able to tolerate the drug well in the first couple months of taking it, compared with those who did not respond as favorably. Patients with either of two variants were three times more likely to require increases in heart failure medications to treat worsening symptoms after they began taking beta-blockers and required more frequent follow-up. The National Institutes of Health, Orchid Biosciences Inc. and UF funded the study, which was conducted at UF and the University of North Carolina at Chapel Hill.

"These very small, subtle differences that occur in the gene are producing enough differences in the action of the drug that we're able to see that in the way the patients tolerate the beta-blocker," Johnson said.

The researchers also noted that genetic variations influenced the degree to which the heart returned to a more normal shape and size after a patient began taking the drug. In fact, patients in one subgroup out of four studied actually fared worse - the heart continued to enlarge.

"Our data suggest that you might be able to use genetic information to identify, before therapy, those people who are going to have difficulty," Johnson said. "That would allow the physician to really focus in on those patients and monitor them very closely. So it potentially provides the physician with a better understanding of those people who are going to need a lot of close attention, so that they can focus on those, and then those who are probably going to do fine might be managed in a simpler way."

UF researchers say the findings justify the need for a larger study to better define the role of genetics in how beta-blockers are tolerated. Scientists also will need to scrutinize additional genes to determine their role, if any, in the process.

"I think it does provide some early evidence that we need to begin looking at patients as individuals and not just group everybody together," Johnson said. "We certainly don't consider this to be the final answer, but we think it's an important first piece of information that hopefully will lead to further studies that then will really allow us to begin to use genetic information in the clinical setting to help make better decisions about how to use these drugs in heart failure patients."

The research findings suggest that the gene variants that determine initial tolerability to beta-blockers and the heart's structural and functional response to the treatment also might affect outcomes long term, said Michael Bristow, M.D., Ph.D., co-director of the University of Colorado Cardiovascular Institute in Aurora, Colo.

"This raises the possibility that the clinical response to at least some beta-blocking agents can be substantially enhanced by selection of patients who have the 'hyper-responsive' Arg389Arg beta-1 adrenergic receptor gene variant," Bristow said. "Although additional data from large clinical trials will be required to confirm this hypothesis, this is potentially a good example of how a functionally important genetic variant can alter therapeutic responses, and how such effects could be exploited in treatment strategies as well as the drug development process."