Duke Researchers Uncover Genetic Link to Stroke after Heart Surgery
DURHAM, N.C. -- Duke University Medical Center researchers have discovered that patients who have two specific gene variants are more than three times as likely to suffer a stroke after heart surgery.
Furthermore, since the two implicated genes are involved in the body's immune response to insult or injury, the researchers said that their findings strongly suggest that inflammation plays an important role in post-operative stroke.
The researchers said that if the findings are confirmed by more extensive studies, they could become part of a battery of genetic tests to better identify the risk to patients of stroke after surgery.
"Despite all our advances in improving outcomes after cardiac surgery over the decades, stroke remains a significant and debilitating complication," said Duke cardiothoracic anesthesiologist Hilary Grocott, M.D., whose study results were published early on-line in the journal Stroke. The study was supported by the National Institutes of Health and the American Heart Association.
"As the population of patients getting cardiac surgery continues to age, it is important for us to better understand all the factors that impact mortality and the quality of life for these patients," he continued. "Discovering that these two genes are linked to stroke after heart surgery is an important first step that should now be validated by larger studies."
While it is still too early to change clinical practice based on the findings of the Duke team's findings, Grocott said that in the not-too-distant future physicians will be better able to define a specific patient's risk for adverse outcomes after heart surgery based on a spectrum of genetic and clinical information.
"When discussing the risks and benefits of surgery, it is important to patients to know whether they are at a higher or lower risk," he said.
For their study, the researchers selected 26 genes implicated in past non-surgical studies as possibly playing a role in the incidence of stroke. The genes identified regulate three general processes – coagulation, inflammation and lipid metabolism.
After identifying the candidate genes, the researchers then consulted a databank of 1,635 patients enrolled in an ongoing Duke study on the role of genetics in cardiac surgery outcomes. Of those patients, 28 (1.7 percent) suffered a stroke after surgery. Nationally, the reported incidence of stroke after heart surgery is approximately two percent but can vary widely, Grocott said.
The researchers then analyzed blood samples to determine whether specific variants, known as polymorphisms, of the 26 candidate genes, either alone or in various combinations were associated with stroke.
While they found that no individual polymorphism was linked to stroke, the team did find that patients with a specific combination of polymorphisms in genes responsible for the production of C-reactive protein (CRP) and interleukin-6 (IL-6) suffered stroke at more than a three times higher rate. CRP is a protein released into the bloodstream as a natural reaction to infection, fever or other injury, while IL-6 is a protein that regulates the intensity of the immune response.
Of the patients enrolled in the study, 36 percent had the polymorphism pair in question – 3.09 percent of those patients suffered a stroke, while only 0.95 percent of patients without the pair suffered a stroke.
"We know that a patient's genetic makeup plays a major role in so many diseases, there's no reason to believe that cardiac surgery is any different," Grocott said. "We also know that cardiac surgery is one of the biggest pro-inflammatory stimuli known, so the fact that inflammation is involved is not surprising."
While the role of inflammation was not surprising, Grocott said the team found it significant that they found no links to genes involved in the blood coagulation pathway. "To see these patients get strokes without a thrombotic polymorphism is somewhat of a novel finding in itself," he continued.
Grocott said that since this polymorphism pair appears to be present in more than one-third of the population undergoing heart surgery, further study is needed not only to better understand the underlying mechanisms involved but to determine if new approaches to minimize the inflammatory response in patients identified at high risk could impact outcome.
Two earlier Duke studies this year have found genetic links to other adverse outcomes after cardiac surgery. One study found polymorphisms linked to kidney damage after heart surgery, while another study uncovered polymorphisms that can help predict which patients are more likely to suffer bleeding episodes after heart surgery.
Other members of the team, all from Duke, are: William White, Richard Morris, Ph.D., Mihai Podgoreanu, M.D., Joseph Mathew, M.D., Debra Schwinn, M.D., and Mark Newman, M.D. Dahlia Nielsen, Ph.D., now at N.C. State University, was also a member of the team.
All of the researchers are members of the Perioperative Genetics and Safety Outcomes Study (PEGASUS), an ongoing longitudinal and prospective study whose goal is improving the outcomes of cardiac surgery.