"In our investigation of acute coronary syndrome (ACS) patients discharged on beta-blocker therapy, we were able to associate 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 biology and pharmacology at the School of Medicine. "We identified high-, intermediate- and low-risk groups that had particular variations in these genes, which interact with beta-blocker drugs."
Patients in the high-risk group had a five times higher risk of death than those in the low-risk group according to the hazard ratio, a statistical measure of risk. If further research indicates that beta-blockers are ineffective or create a higher risk in patients with certain variations of beta-adrenergic receptor genes, physicians may modify treatment to improve survival in these patients, according to McLeod.
"These data, while provocative, should not immediately alter current practice," says lead author David E. Lanfear, M.D., formerly of the School of Medicine and now a member of the cardiology staff in the heart failure and cardiac transplant section at Henry Ford Hospital in Detroit. "Further investigation is needed to determine whether the effect seen is due to the lack of efficacy of beta-blockers in higher-risk patients or if genotype alone is responsible for a worse outcome."
Beta-adrenergic receptors in the sympathetic nervous system respond to adrenaline, but beta-blocker drugs block this interaction, slowing the heartbeat and lowering blood pressure to relieve stress on the heart. They also block impulses that can cause rhythm disturbances.
"Long-term therapy with beta-blockers is standard care for heart patients," Lanfear says. "Data from patients with acute myocardial infarction have shown that beta-blockers are generally effective. They are known to decrease the size of the infarct and seem to prolong survival, on average."
Recent research, however, reveals that variations in the beta-adrenergic receptor genes affect the benefit of beta-blockers in heart patients. Data indicate that variations of the genes influence such parameters as blood pressure response in hypertensive patients and heart function in heart failure patients.
"But this is the first time that anyone has shown that these genetic variations affect survival," McLeod says.
Humans have two types of beta-adrenergic receptors, beta-1 and beta-2. In this study, the researchers found no difference in survival associated with variations of the beta-1 gene. But variations in the beta-2 gene significantly determined length of survival for ACS patients who were taking beta-blockers. For those patients not taking beta-blockers, variations in the beta-adrenergic receptor genes showed no evidence of effect on survival, although small sample size makes this result uncertain.
The beta-2 gene commonly has two points of sequence variation within the human population--for most of the population, the gene's coding sequence will be identical from person to person at all other points. Thirty-nine percent of the population possess a set of beta-2 genes with a C base at position 79, and 16 percent possess at set 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 genetic variations constituted the high-risk group--by the end of three years, 20 percent of this group had died. By comparison, patients who had G bases at position 79 or 46 on both chromosomes had only a six percent mortality rate and were termed low-risk. Patients with any other combination of beta-2 gene variations had an overall 11 percent risk of death after three years and were classified as an intermediate-risk group.
"Our study makes it clear how powerful genetic analysis is and how important it can be for individual patients," says senior author John A. Spertus, M.D., director of cardiovascular education and outcome research at the Mid America Heart Institute in Kansas City, Missouri, professor of cardiology at the University of Missouri, Kansas City and adjunct professor of medicine at Washington University School of Medicine. "It gives a hint of what medical practice will be like down the road when we can put such knowledge to practical use every day."The study consisted of 735 ACS patients from two Kansas City, Missouri hospitals. Patients' average age was 60, and 81 percent of the patients were on beta-blocker therapy. Next, the researchers will conduct a larger study of 4,500 heart patients from 20 centers throughout the country.
Called TRIUMPH (Translational Research Investigating 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 of life and survival after a heart attack. Similar to the current study, these data will be analyzed on the basis of genetic variations in the beta-adrenergic receptor genes and other potentially important genes.
"The new study's ability to assess the effect of genotype on patients' health will benefit from the larger sample size and greater diversity of patients," Spertus says. "It's really an exciting and unique collaborative venture that builds a strong relationship between researchers in Kansas City and St. Louis."
The TRIUMPH registry recruits patients through the Cardiovascular Outcomes Research Consortium (CORC) headed by Spertus who will partner with McLeod and basic scientists led by Daniel P. Kelly, M.D., the Alumni Endowed Professor of Cardiovascular Diseases at Washington University School of Medicine, director of the Center for Cardiovascular Research and a cardiologist at Barnes-Jewish Hospital. The current study is the first set of findings from this collaboration.