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Genetic Testing Can Predict Beta Blocker Effectiveness According to University of Pittsburgh Study

PITTSBURGH, March 27, 2001 — The effectiveness of beta blockers in improving the survival of congestive heart failure patients can be predicted by genetic testing of the angiotensin converting enzyme (ACE) gene, according to a University of Pittsburgh School of Medicine study published in the March 27 issue of Circulation, a publication of the American Heart Association.

Beta blockers are drugs used to treat congestive heart failure, a progressive disease in which the heart's muscle becomes weakened after it is injured from a heart attack or high blood pressure and gradually loses its ability to pump blood to supply the body's needs. Previous studies have shown that beta blockers are more effective in some patients than in others.

Many important genes occur in the general population in multiple variations (or alleles), some of which may alter how the gene functions. A common variation of the ACE gene, the "ACE D" or deletion allele, is missing a small section of DNA. This results in patients having higher levels of the hormone angiotensin II, which raises blood pressure. In patients with heart failure, higher levels of angiotensin II lead to a worsening of symptoms by causing blood vessels to constrict, putting an increased strain on the heart muscle.

"Despite this association between the D allele and higher angiotensin II levels, its role as a cardiac risk factor for heart failure progression remains controversial," said Dennis McNamara, M.D., assistant professor of medicine at the University of Pittsburgh School of Medicine, director of the heart failure section at the University of Pittsburgh Medical Center Cardiovascular Institute and principal investigator in the study.

The prospective study, called Genetic Risk Assessment of Cardiac Events (GRACE), was designed to look at the effects of genetic variation on survival in patients with heart failure, and in particular the impact of genetics on the effectiveness of drug therapy. The study followed 328 patients with heart failure due to a weakened heart muscle for an average of 21 months. Their mean age was 56. In terms of their medical therapy at the time of their entry into the study, 87 percent of patients were treated with ACE inhibitors, nine percent with angiotensin receptor blockers and 37 percent with beta blockers.

Since chromosomes exist in pairs, everyone has two copies of the ACE gene, one inherited from their father and one from their mother. The study classified patients into three groups (or genotypes) based on whether they had two copies, one copy or no copies of the ACE D allele. Survival of those patients during the study period was compared by genotype for the entire group, and separately in patients with, and patients without, beta blocker therapy.

For the entire study group, the one-year survival rate was poorer for patients with two D alleles (75 percent) than for patients with one D allele (77 percent) or no D alleles (94 percent).

"This negative impact of the ACE D allele on survival was only seen in patients not on beta blocker therapy, and was virtually eliminated by therapy with these agents," said Dr. McNamara. "Importantly, the third of the patients with two copies of the D allele (DD genotype) had the maximum benefit from beta blocker therapy, as use of these agents for these patients was associated with a dramatic improvement in survival. The benefits of beta blockers in the remaining patients was far less apparent. These findings suggest a potential pharmacogenetic interaction between the ACE D and beta blocker therapy in the determination of heart failure survival."

Despite similar demographics and functional class by beta blocker therapy status, Dr. McNamara writes, the absence of beta blocker randomization at baseline makes the investigation of pharmacogenetics in the study exploratory in nature.

"However, the hypothesis suggested by the data that genetic heterogeneity influences the effect of beta blocker therapy on survival can and should be re-evaluated in the context of ongoing multi-center randomized trials," he said.

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