Individual’s Genes May Dictate Better Heart Failure Treatment

Researchers found that individuals with two copies of a particular form of an enzyme that increases blood pressure fared the worst with heart failure but fared the best with beta-blockers. This finding could lead to targeted individual treatment based on genetic makeup.

Angiotensin-converting enzyme or ACE activates a hormone to increase blood flow to vital organs. When the enzyme signals the need for higher blood pressure for the kidneys, it causes the failing heart to work harder. Eventually the heart wears out and a heart transplant is required to avoid death. Everyone has two copies of an ACE gene, which can take one of two forms – or alleles – the insertion (I) and the deletion (D) alleles, based on whether one small section of the gene is missing. The deletion (D) form of the gene was affected by beta blocker therapy.

“Having this D allele seemed to be a risk factor for doing poorly overall, but if you were on beta-blocker therapy this hazard was eliminated,” says Dennis M. McNamara, M.D., study leader and director of the heart failure section at the University of Pittsburgh Medical Center. “Those with two copies of the D allele (DD) clearly got the most benefit from beta-blocker therapy.”

McNamara is a leader in a new field of research called pharmacogenetics, which studies the interaction of drugs and genes.

“This is the first study to look at a very common genetic trait and its interaction with a very common therapy for heart failure,” he says. “One of our most significant findings was that the benefits of beta-blocker therapy in heart failure survival seem to be much different within the three classes of patients we defined genetically.”

Of the 328 heart failure patients in this study, 32 percent had two D alleles, 21 percent had two I alleles and 47 percent had one D and one I allele. As in the general population, about 79 percent had at least one D allele.

Most of the patients (87 percent) were on ACE-inhibitor therapy – drugs that block the enzyme’s effect, reducing the heart’s workload. In addition, 37 percent also took beta-blocker drugs, which reduce the heart’s output of blood.

Researchers followed the individuals for two years and found that among those who did not receive beta-blockers, only 48 percent in the DD group survived for two years without a transplant, compared to 81 percent among patients who had two I alleles (II). However, in those treated with beta-blockers, 77 percent of the DD group were alive and transplant-free after two years, virtually the same as the 70 percent found in the II group.

Larger studies are needed before genetics could be brought into treatment decisions, McNamara says. One limitation of the current study was that treatment was not randomly assigned. “My excitement about it remains that we will see targeting of therapy based on genetics in the next five or 10 years,” he says. “I have patients who that may be on six to eight classes of drugs and new ones are coming out all the time. We’ve got to find a way to get the right drugs to the right people and I believe genetics will be a key component of that targeting.” In an accompanying editorial, Dan M. Roden, M.D., professor of medicine and pharmacology and director of the division of clinical pharmacology at Vanderbilt University School of Medicine in Nashville, Tenn., and Nancy J. Brown, M.D., associate professor of medicine and pharmacology, praise the Pittsburgh team, but say too many questions remain to base clinical decisions on genetics.

For instance, although studies have consistently shown that DD individuals have more ACE activity, the mechanisms for it remain unclear, they write.

In addition, a number of small differences among the three groups in this study could have affected the results, such as the difference in the number of people taking ACE-inhibitors. There is also the possibility that the genetic differences studied here are linked to or interact with other genes with unknown effects.

“The new and intriguing finding in the present study was that the poor prognosis conferred by the D allele was improved ... in patients treated with the beta-blockers,” they write. More data from larger studies will help clarify the situation. That will take the cooperation of clinicians, so making them aware of pharmacogenetics’ potential is crucial, according to the editorial.

“McNamara and his colleagues are to be congratulated for taking an important first step in this direction,” they write.

McNamara’s co-authors include Richard Holubkov, Ph.D.; Karen Janosko, R.N., M.S.N.; Amy Palmer, M.A.; Jue J. Wang, M.S.; Guy A. MacGowan, M.D.; Srinivas Murali, M.D.; Warren D. Rosenblum, M.D.; Barry London, M.D., Ph.D.; and Arthur M. Feldman, M.D., Ph.D.

The work was funded in part by the National Heart, Lung and Blood Institute.