Recovery Act funding aids the search for cures to Americans’ heart disease
By Terry Taylor
February 19, 2011
Susan R. Heckbert, M.D., Ph.D.
Professor, Department of Epidemiology, University of Washington School of Public Health, Seattle Investigator, Cardiovascular Health Research Unit, University of Washington School of Medicine, Seattle
Marty could never forget her first experience with it. Her heart suddenly took off like a racehorse, leaving her gasping for breath and terrified; then she was in the hospital with the doctors running test after test. The diagnosis? Lone atrial fibrillation, a condition in which the heartbeat is out of rhythm, but not due to any detectable heart disease. The tests found no underlying heart problems. Marty was only 55 years old. What was the trigger? In her case, probably the stress of her recent divorce and then losing her job. What sets off lone atrial fibrillation varies, however, and is highly specific for each individual. What’s the solution? So-called “antiarrhythmic” drugs are usually the first line of treatment, but the symptoms recur in 60 to 80 percent of patients within their first year of therapy. Is a more effective treatment possible?
Marty is one of more than 2 million Americans affected by atrial fibrillation, although as a patient in her fifties she is younger than most. The condition is a known cause of stroke and can cause worrisome symptoms such as a fluttering or racing heartbeat and fatigue. Dr. Susan Heckbert is looking for the causes of this and other types of heart disease—and not only in the United States, where heart problems are the leading cause of death. Heart disease is rampant throughout the Western world and is becoming more common even in developing countries as populations move toward a more Western lifestyle and diet.
Heckbert, a medical doctor and an epidemiologist, looks at population-wide cardiovascular questions. Can we predict who will have heart problems? Can we find new and better ways to target medicines and other interventions for those persons?
Heckbert’s Recovery Act funding has helped make it possible to develop an innovative research program to look at atrial fibrillation, using several approaches, with additional resources likely not otherwise available. For example, she used part of her Recovery Act grant to hire a new graduate student research assistant, Paul Jensen, and to retain several research staff members. She also used the funds to purchase computer systems for data analysis and a minus-70-degree-centigrade freezer for specimen storage.
Large Genome Study Finds Possible New Drug Target
In one recent study, Heckbert and her team at the Cardiovascular Health Research Unit worked with collaborators at the Massachusetts General Hospital in Boston and the Cleveland Clinic, investigators in the Atherosclerosis Risk in Communities Study, and researchers in Germany to locate 1,335 individuals with lone atrial fibrillation and 12,844 unaffected individuals for comparison. The scientists conducted a genome-wide association study (GWAS), in which genetic variation across the entire genomes of hundreds or thousands of people is examined and compared to see if any specific variability is common to those with a particular disease or condition, while rarely or never seen in people without the condition.
Heckbert’s team found a small variation in patients with lone atrial fibrillation in a gene called KCNN3. This gene makes a protein involved in the heart’s electrical system—the heartbeat control system. People with the small difference that Heckbert and her team found in this gene are more likely to have lone atrial fibrillation.
Heckbert is quick to point out that this does not mean that physicians will have a new medicine to treat atrial fibrillation in the near future. As she explains, “The first step is finding that a variation is related to a disease. Then you can work toward finding a therapy that targets the variation. We have taken that first step.”
“Patients with lone atrial fibrillation are the ideal population in which to look for possibly important genetic factors,” Heckbert elaborates. “They are aged 65 years and younger, and they don’t have clinical evidence of structural heart disease, which atrial fibrillation usually travels with. Even so, they develop atrial fibrillation.” With their relative youth and lack of any other heart disease, it may be easier to detect genetic causes for atrial fibrillation in this population.
“The overall risk of atrial fibrillation keeps rising as people age. Looking at the lone atrial fibrillation group gave us the opportunity to find something possibly applicable to the older population as well,” Heckbert points out. She adds, “We have now gone beyond this group in our studies and are continuing the work in the older population. Finding this genetic variation in more typical, older atrial fibrillation patients would be really exciting.”
ARRA Helps Identify Other Interventions
In related work, also made possible by ARRA funding, Heckbert and her team worked with colleagues associated with the Framingham Heart Study in Massachusetts to apply a risk algorithm for atrial fibrillation to a population different from the one used to develop the original algorithm. A risk algorithm may be thought of as a cluster of factors that increase the risk for a condition. In other words, patients with some or all of the factors are likely to be at increased risk for the condition. In the case of atrial fibrillation, these factors include age, sex, body mass index (a measure of how overweight or obese a person is), heart failure, blood pressure, and treatment for high blood pressure. The algorithm was developed in a population of white Americans. The question Heckbert and her colleagues asked was whether the same risk factors predict atrial fibrillation in other populations.
“Sometimes when you develop a risk algorithm, it works well in the group it was developed in, but not in other groups,” Heckbert explains. “The question is, does it apply in other settings? It turns out that this one does work and quite well.” The same collection of risk factors predicted atrial fibrillation in an entirely different population that included both whites and African Americans. “This algorithm is not a perfect predictor, but it gets us closer.” Heckbert also points out that sex and age can’t be changed, but some of these factors, such as blood pressure and body mass index, can be modified. A person’s risk can be lowered—if the patient is known to have the risk. “That’s how the risk algorithm helps,” says Heckbert.
In yet another approach to the knotty problem of atrial fibrillation, Heckbert and her coworkers at the University of Washington looked at diabetes as a risk factor. They studied 1,410 people with newly diagnosed atrial fibrillation and compared them with 2,203 people without atrial fibrillation. Previous studies of a possible relationship between diabetes and atrial fibrillation had given mixed results.
Heckbert and her group found that a larger percentage of those with atrial fibrillation had confirmed diabetes than did those without atrial fibrillation. Looking closer, the study found that the risk for atrial fibrillation increases by 3 percent for each year following diagnosis of diabetes. Furthermore, the risk increases with poor glycemic control, as measured by hemoglobin A1c, a test used to determine blood sugar control over several months. The higher a patient’s hemoglobin A1c, the higher the risk for atrial fibrillation.
Looking to the Future
These three studies mark important advances in our knowledge of atrial fibrillation, and these advances were made possible, in part, by Recovery Act funding. Finding a genetic variation associated with atrial fibrillation is a leap forward—even if it does not guarantee a cure next week or next year. It gives researchers a place to start in the search for new and better medicines.
Meanwhile, leveraging the discovery of the strong relationship between diabetes and atrial fibrillation will have immediate impact. People find it difficult to lose weight, reduce blood pressure and control blood sugar levels, but in doing so, they may be able to lower their risk for atrial fibrillation today, while looking forward to further discoveries.
Recovery Act Investment: “Atrial Fibrillation: Incidence, Risk Factors and Genetics”; Susan Heckbert, University of Washington; 2009: $627,821 (2R01HL068986-05A2); 2010: $566,313 (5R01HL068986-06). Funded by the National Heart, Lung and Blood Institute.
Publications:
Dublin S et al. Diabetes mellitus, glycemic control, and risk of atrial fibrillation. Journal of General Internal Medicine, 2010;25(8):853–858.
Ellinor PT et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nature Genetics, 2010;42(3):240–244.
Schnabel RB et al. Validation of an atrial fibrillation risk algorithm in whites and African Americans. Archives of Internal Medicine, 2010;170(21):1909–1917.
