Variants of two genes involved in the inflammatory system linked to cognitive decline after heart surgery

May 2 2007

Variants of two genes involved in the inflammatory system appear to protect patients from suffering a decline in mental function following heart surgery.

Duke University Medical Center researchers believe their findings could help physicians identify patients at risk of suffering mental decline after heart surgery and raises the possibility that these patients could be treated with drugs that are known to dampen the inflammatory response.

Six years ago, the Duke researchers demonstrated that 42 percent of patients who underwent coronary artery bypass surgery had measurable cognitive decline five years after their procedure. Since that finding, the team has been investigating possible reasons for this decline.

The researchers selected known variations in 37 genes that previous studies had implicated in various impairments of cognitive and mental function. When they looked at more than 500 heart surgery patients and correlated cognitive decline with the patient's genetic makeup, they discovered that patients with two specific variants were less likely to have problems with areas of cognitive function such as memory, attention and concentration.

"While bypass surgery has saved millions of Americans with coronary artery disease, many patients and families find that cognitive decline after surgery has reduced their quality of life," said Duke cardiothoracic anesthesiologist Joseph Mathew, M.D., lead investigator of the study reported online Tuesday, May 1, in the Journal of the American College of Cardiology. The study was supported by the National Institutes of Health and the American Heart Association.

"The two gene variants we found were involved in some manner with the inflammatory system, raising the possibility that therapies given during surgery aimed at the controlling the inflammatory response would be protective," Mathew said. "Also, our results provide additional evidence for a genetic basis for the cognitive deterioration seen after heart surgery."

The researchers found that patients with variants in genes for C-reactive protein and P-selectin were less likely to suffer cognitive decline than were patients without the variants. C-reactive protein plays an important role in the body's initial response to injury, and studies have shown that high levels of the protein put patients at higher risk for cardiovascular disease and stroke. P-selectin is a molecule that helps recruit circulating white blood cells to the site of an injury.

For their analysis, the researchers gave 513 heart patients at Duke University Hospital a battery of cognitive exams before heart surgery and then six weeks later. They found that patients with the variation of the C-reactive protein gene were 20.6 percent less likely to suffer mental decline, and patients with the P-selectin variant had a 15.2 percent risk reduction. The incidence of deficit in patients with both gene variants was 17 percent compared to 43 percent in patients who had neither variant.

Furthermore, patients with the two gene variants had significantly lower levels of C-reactive protein in their bloodstream and lower P-selectin expression, and the researchers said this factor may provide a biological basis for the protective effect they observed.

"Although we have made significant progress in minimizing the adverse events related to cardiac surgery, little progress has been made in reducing postoperative cognitive decline," said Mark Newman, M.D., chairman of anesthesiology and senior member of the research team. "While we know that there are many factors involved in this phenomenon, the results of this study provide insight into the genetic factors that influence cognition and may translate into more precise identification of at-risk patients."

Coronary artery bypass grafting surgery is performed more than 600,000 times a year in the United States for the treatment of coronary artery disease. Typically, surgeons use pieces of blood vessels from other parts of the body to ,bypass, clogs in coronary arteries, thereby restoring blood flow to the heart.

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