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Findings Reported From the First Study to Link Patients' Genetic Profiles With Their Clinical Outcomes After Cardiac Operations

Posted on: Tuesday, 18 October 2005, 15:00 CDT

SAN FRANCISCO, Oct. 18 /U.S. Newswire/ -- Investigators from Beth Israel Deaconess Medical Center, Boston, are beginning to learn how patients' genetic makeup may predict their outcomes after undergoing cardiac operations. A study presented at the 2005 Clinical Congress of the American College of Surgeons is the first to find differences in gene expression levels in peripheral tissue in diabetic patients versus non-diabetic patients in terms of their response to cardiac operations and the need to be placed on the heart-lung machine. "Previously, we have known that diabetic patients are more prone to complications following heart surgery, necessitating the use of the heart-lung machine. This study shed new light by demonstrating that diabetic patients are qualitatively and quantitatively different at the gene expression level," Basel Ramlawi, MD, a fellow in cardiovascular surgery, Harvard Medical School and Beth Israel Deaconess Medical Center said.

The study found that muscle from non-diabetic patients exhibited 626 upregulated and 348 downregulated genes after cardiac surgery. In contrast, muscle from diabetic patients exhibited a different set of 420 upregulated genes and 473 downregulated genes. In particular, diabetic patients had lower levels of the TR3 gene (a receptor that mediates the function of cells that line the blood vessels), which was associated with postoperative weight gain. "This endothelial function gene, which is differentially expressed in diabetic patients, may play a role in the way blood vessels release fluid into the surrounding tissue. In that way, the difference in gene expression may be related to the propensity of diabetic patients to gain weight and retain water after surgery, which in turn causes complications, such as edema (excessive fluid buildup) or changes in the permeability of blood vessels in the periphery," Dr. Ramlawi said. "The study is at the preliminary stages of investigation, and only gives us a clue in terms of the difference in response to heart surgery and the heart-lung machine, in particular, among diabetic patients," he added.

This line of research also may apply to outcomes for other patients who undergo cardiac surgery. The investigators at Beth Israel Deaconess Medical Center are looking at genes that may be correlated with changes in neurological and cognitive function following cardiac surgery so that one day surgeons may be able to identify the patients who are susceptible to neurological or cognitive problems after surgery and can institute drug or other preventive strategies ahead of time. "Our hope is that we can predict which patients will suffer certain complications by looking at their genetic profile and be able to target treatment based on that profile," according to Frank Sellke, MD, FACS, professor of surgery at Harvard Medical School.

Dr. Sellke speculated that white blood cells obtained through a simple blood test before surgery might be subjected to analysis using microarray technology (an automated method of screening for the activity of as many as 30,000 different genes in DNA samples) to find those patients who express the genes associated with such complications as systemic inflammatory response syndrome (a condition related to sepsis that is characterized by symptoms similar to shock, including low blood pressure, rapid heart beat and respiratory rate), neurological or cognitive dysfunction, or stroke. These patients then would be given drugs to counteract their predisposition toward inflammation. "Our work on this study is at the interface between out-comes research and genomics. Outcomes research tries to identify risk factors for certain poor outcomes or complications. This study takes that research a step further to focus on the genetic profile of patients and find patients who are more likely to develop certain complications so we can direct treatment to improve outcomes," he explained. "It is still very preliminary, but so far the results are encouraging," Dr. Sellke added.

In the study, genetic material in ribonucleic acid (RNA), which provides a level of expression of genes, was isolated in skeletal muscle that had been obtained from five non-diabetic and five diabetic patients. RNA was analyzed in a microarray that evaluated the over- and under-expression of each of a total of 12, 625 genes. Differences in gene expression in the two groups of patients were correlated with physiological indicators of suboptimal outcome, such as weight gain and changes in systemic vascular resistance, body temperature, and vasopressor (a substance that constricts blood vessels and raises blood pressure) requirements. Other than the need for insulin among diabetic patients, both groups of patients were similar in every other respect, Dr. Ramlawi said.

In future experiments, Dr. Ramlawi and his colleagues will seek to confirm the relation-ship between genetic expression and complications in diabetic patients. "The first step is to find out with certainty which genes are differentially expressed using laboratory technique and try to modify gene expression that is particular and specific to diabetic patients," he said. "The next step would be to tailor treatment to prevent the complications that are specific to diabetic patients. By identifying genes which are differentially expressed in diabetics and non-diabetics, we may come up with new therapeutic solutions that would tailor treatment to diabetic status and improve and affect the activity of particular genes," Dr. Ramlawi concluded. Analysis of genes expressed in neurological and cognitive function is just beginning.

"If you're looking at thousands of genes, you're going to find differences in gene expression. What to make of that, we don't know yet. We have to do many more studies," Dr. Sellke said. Also involved in the study were Tanveer Khan, MD; Marc Ruel, MD, MPH; Pierre Voisine, MD; Cesario Bianchi, MD, PhD; John Liddicoat, MD; and Munir Boodhwani, MD.

http://www.usnewswire.com

Source: U.S. Newswire

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