Gene Variants Predict Heart Muscle Damage
Duke University Medical Center scientists have found that patients with six specific variants of genes involved in the body's immune response are significantly more likely to suffer damage of heart tissue after cardiac surgery.
These findings are important because current analytical methods cannot reliably predict who will be likely to suffer from myocardial infarction (MI), or heart tissue death after cardiac surgery. It is estimated that between 7 and 15 percent of patients undergoing coronary bypass surgery will suffer from a subsequent MI, the scientists said.
"We have identified six gene variants, or polymorphisms, that are significantly associated with the incidence of post-operative myocardial infarction following cardiac surgery," said Duke cardiothoracic anesthesiolologist Mihai Podgoreanu, M.D., who presented the results of the Duke study Nov. 13, 2005, during the annual scientific session of the American Heart Association (AHA). The analysis was supported by the National Institutes of Health and the AHA. "Collectively, these variants can explain about 75 percent of the variability in heart damage in patients undergoing surgery."
"These findings should help clinicians identify those patients who are at highest risk before surgery, so they can better inform patients and take appropriate precautions during and after surgery," Podgoreanu continued. "Additionally, these findings validate that specific proteins are involved in the damage to heart tissue, which gives us rational targets for potential new drugs."
Of the six polymorphisms, four are directly associated with the damage, while the other two polymorphisms are found in genes that would normally have a protective effect.
During a bypass procedure, the heart is typically stopped for a period of time to allow a stable field of operation for the surgeons, and its function replaced by the heart-lung machine. During this time, the heart is bathed in a cold slushy solution to reduce the heart's metabolic needs.
"However, despite all our best efforts to protect the heart during surgery, there is always some damage as the heart re-warms and the blood flow returns to the muscle," Podgoreanu said. This damage is known as reperfusion injury.
Clinicians can determine the extent of damage to heart muscle by measuring the levels of a specific enzyme known as creatine kinase-MB (CK-MB), which leaks into the bloodstream as heart muscle cell walls break apart as a result of damage or death.
The scientists began by identifying 48 known polymorphisms of 23 candidate genes that are all involved with the body's immune response. They then enrolled 432 patients undergoing cardiac surgery. Blood samples were taken 24 hours after surgery. Patients were considered to have suffered a post-operative MI if their CK-MB levels were at least ten times higher than the upper limit of normal. Of the patients, 52, or 12 percent, were considered to have suffered an MI.
Using a two-step genetic analysis, the scientists looked for genetic difference between those patients who suffered a post-operative MI and those who did not.
"We found it interesting that each of the six polymorphisms individually had only a modest effect, but when taken together, the combined effect was significant," Podgoreanu said. "If an individual is unfortunate enough to have this combination of genetic factors, they will likely experience an exaggerated and negative response to reperfusion."
Specifically, the deleterious polymorphisms were in genes that code for the production of four different proteins: interleukin-6 (IL-6), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM1) and lipopolysaccharide-binding protein (LBP).
IL-6 is a protein that regulates the intensity of the immune response, and CRP is a protein released into the bloodstream as a natural reaction to infection, fever or other injury. ICAM-1 allows the white cells to attach to the inner lining of the blood vessels where they inflict damage. LBP regulates the body's response to bacteria normally living in the gastrointestinal tract that can release endotoxins into the bloodstream as a result of the action of the heart-lung machine.
The final polymorphism - in a gene that codes for the enzyme catalase - appears to be involved in mediating the effects of oxidative stress. The normal version of the gene produces proteins that can blunt the negative effects of oxygen free radicals, while the polymorphism is unable to do so effectively. It is well established that heart muscle cells are placed under oxidative stress during reperfusion.
Podgoreanu's paper is one of five finalists for the AHA's annual Vivien Thomas Young Investigator award. The winner will be announced at the meeting.
Earlier this year, members of the same research team found that patients with a different set of polymorphisms were at a two to four times more likely to suffer kidney damage as a result of major heart surgery. In another study this year, the team found variants of genes that control clotting and the contractility of blood vessels can double the ability to predict those heart surgery patients at greatest risk of bleeding after surgery.
Other members of the team, all from Duke, are: William White, Joseph Mathew, M.D., Mark Stafford-Smith, M.D., Ian Welsby, M.D., Mark Newman, M.D., and Debra Schwinn, M.D. All are members of Duke's Perioperative Genetics and Safety Outcomes Study (PEGASUS) team.