Survival Of Heart Patients On Beta-blockers Varies Greatly With Genetic Variation

"In our investigation of acute coronary syndrome(ACS) patients discharged on beta-blocker therapy, we were able toassociate risk of death with the characteristics of the patients'beta-adrenergic receptor genes," says co-author Howard L. McLeod,Pharm.D., professor of medicine, of genetics and of molecular biologyand pharmacology at the School of Medicine. "We identified high-,intermediate- and low-risk groups that had particular variations inthese genes, which interact with beta-blocker drugs."

Patients inthe high-risk group had a five times higher risk of death than those inthe low-risk group according to the hazard ratio, a statistical measureof risk. If further research indicates that beta-blockers areineffective or create a higher risk in patients with certain variationsof beta-adrenergic receptor genes, physicians may modify treatment toimprove survival in these patients, according to McLeod.

"Thesedata, while provocative, should not immediately alter currentpractice," says lead author David E. Lanfear, M.D., formerly of theSchool of Medicine and now a member of the cardiology staff in theheart failure and cardiac transplant section at Henry Ford Hospital inDetroit. "Further investigation is needed to determine whether theeffect seen is due to the lack of efficacy of beta-blockers inhigher-risk patients or if genotype alone is responsible for a worseoutcome."

Beta-adrenergic receptors in the sympathetic nervoussystem respond to adrenaline, but beta-blocker drugs block thisinteraction, slowing the heartbeat and lowering blood pressure torelieve stress on the heart. They also block impulses that can causerhythm disturbances.

"Long-term therapy with beta-blockers isstandard care for heart patients," Lanfear says. "Data from patientswith acute myocardial infarction have shown that beta-blockers aregenerally effective. They are known to decrease the size of the infarctand seem to prolong survival, on average."

Recent research,however, reveals that variations in the beta-adrenergic receptor genesaffect the benefit of beta-blockers in heart patients. Data indicatethat variations of the genes influence such parameters as bloodpressure response in hypertensive patients and heart function in heartfailure patients.

"But this is the first time that anyone has shown that these genetic variations affect survival," McLeod says.

Humanshave two types of beta-adrenergic receptors, beta-1 and beta-2. In thisstudy, the researchers found no difference in survival associated withvariations of the beta-1 gene. But variations in the beta-2 genesignificantly determined length of survival for ACS patients who weretaking beta-blockers. For those patients not taking beta-blockers,variations in the beta-adrenergic receptor genes showed no evidence ofeffect on survival, although small sample size makes this resultuncertain.

The beta-2 gene commonly has two points of sequencevariation within the human population—for most of the population, thegene's coding sequence will be identical from person to person at allother points. Thirty-nine percent of the population possess a set ofbeta-2 genes with a C base at position 79, and 16 percent possess atset of beta-2 genes with an A base at position 46.

In this study,ACS patients on beta-blockers with either of these two specific geneticvariations constituted the high-risk group—by the end of three years,20 percent of this group had died. By comparison, patients who had Gbases at position 79 or 46 on both chromosomes had only a six percentmortality rate and were termed low-risk. Patients with any othercombination of beta-2 gene variations had an overall 11 percent risk ofdeath after three years and were classified as an intermediate-riskgroup.

"Our study makes it clear how powerful genetic analysis isand how important it can be for individual patients," says seniorauthor John A. Spertus, M.D., director of cardiovascular education andoutcome research at the Mid America Heart Institute in Kansas City,Missouri, professor of cardiology at the University of Missouri, KansasCity and adjunct professor of medicine at Washington University Schoolof Medicine. "It gives a hint of what medical practice will be likedown the road when we can put such knowledge to practical use everyday."

The study consisted of 735 ACS patients from two KansasCity, Missouri hospitals. Patients' average age was 60, and 81 percentof the patients were on beta-blocker therapy. Next, the researcherswill conduct a larger study of 4,500 heart patients from 20 centersthroughout the country.

Called TRIUMPH (Translational ResearchInvestigating Underlying Disparities in Myocardial Infarction Patients'Health Status) and funded in part by the National Institutes of Health,the study will evaluate patients' symptoms, heart function, quality oflife and survival after a heart attack. Similar to the current study,these data will be analyzed on the basis of genetic variations in thebeta-adrenergic receptor genes and other potentially important genes.

"Thenew study's ability to assess the effect of genotype on patients'health will benefit from the larger sample size and greater diversityof patients," Spertus says. "It's really an exciting and uniquecollaborative venture that builds a strong relationship betweenresearchers in Kansas City and St. Louis."

The TRIUMPH registryrecruits patients through the Cardiovascular Outcomes ResearchConsortium (CORC) headed by Spertus who will partner with McLeod andbasic scientists led by Daniel P. Kelly, M.D., the Alumni EndowedProfessor of Cardiovascular Diseases at Washington University School ofMedicine, director of the Center for Cardiovascular Research and acardiologist at Barnes-Jewish Hospital. The current study is the firstset of findings from this collaboration.

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Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA.ß2-adrenergic receptor genotype and survival among patients receivingß-blocker therapy after an acute coronary syndrome. Journal of theAmerican Medical Association, Sept. 28, 2005.

Funding from theAgency for Healthcare Research and Quality, the National Institutes ofHealth Pharmacogenetics Research Network, the Specialized Centers ofClinically Oriented Research (SCCOR) Program of the National Heart,Lung, and Blood Institute and an HFSA Research Fellowship Grantsupported this research.