Genetic variation found that predicts response to heart failure medication
Researchers at the University of Maryland School of Medicine and
the University of Colorado Denver School
of Medicine 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
were published in the week of July 10 online issue of Proceedings
of the National
Academy of Sciences www.pnas.org.
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,” said the study’s principal
investigator, Stephen B. Liggett, MD, 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.”
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. 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,” said Michael Bristow,
MD, PhD, a cardiologist at the CU 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.”
The researchers’ conclusions are based in part on a retrospective look
at data from a placebo-controlled study of the drug bucindolol, during
which 1,040 heart failure patients were followed for up to four years.
The study
volunteers also consented to participate in a genetic sub-study which
involved an analysis of their DNA, a process called genotyping. The
researchers looked
at four parameters: whether the patients had the real drug or the
placebo, and whether they had the Arg-389 receptor or the Gly-389
receptor.
In addition, the researchers examined normal donor hearts as well
as hearts removed from patients who were receiving heart transplants
and discovered that, compared to Gly-389, hearts with two copies of the Arg
gene had a greater
response to an adrenaline-like compound called isoproterenol as well
as bucindolol and several other drugs.
The researchers also looked at the genetic variants and the response
to the beta blocker in black patients compared to whites, and found
that genetics and not race determined who benefited best from the
drug. “We believe
it is inappropriate to use a race-based prescribing approach, because within
any given ethnic or racial population there is a genetic variability with
that group. Therefore, some people will have the response gene and some will
not,” said Liggett.
Heart failure affects nearly 5 million Americans, according to the
Heart Failure Society of America. Less than 50 percent of patients
live past five years after their initial diagnosis and less than 25 percent
are alive
at 10 years. The risks of heart failure include high blood pressure,
a prior heart attack, abnormal heart valves and diabetes. In addition, a large
number
of patients have a form of heart failure called idiopathic cardiomyopathy,
where no predisposing factor can be identified.
Heart failure develops when the heart is not able to pump enough
blood to meet the body’s needs. The heart compensates for this loss
in pumping capacity by growing larger, increasing muscle mass and pumping
faster to increase the heart’s output. These changes typically occur
over a long period of time, masking the problem. Eventually, the
heart and the body cannot keep up with the demands, and the person
begins to experience
the fatigue and breathing problems that often are the first signs
of the disease.
Liggett says one of the main possibilities of the Human Genome Project
and related efforts is the concept of tailoring therapy based on
genetics, a field called pharmacogenetics. “It has not turned out to be so easy,” he
says, “but this is one of the few examples that has come to fruition.”
The study was funded by the National Heart, Lung, and Blood Institute
of the National Institutes of Health and the Department of Veterans
Affairs Cooperative Studies Program.
