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University of Iowa News Release

Dec. 15, 2003

UI Researchers Find Inflammation A Key In Cardiovascular Disease

For more than two decades, health professionals and medical researchers have pointed to cholesterol as a major culprit in the fight against coronary heart disease and heart attack. Public awareness has been raised, and today most Americans have at least had their cholesterol checked. Many people also know about HDL ("good") and LDL ("bad") cholesterol levels and the amount of fat in the foods they eat.

Cholesterol, like blood pressure, is indeed a key to good heart health. Too much LDL cholesterol in the blood can slowly accumulate in the arteries, forming plaque that can clog blood vessels (atherosclerosis) and cause heart attack, stroke and other forms of vascular disease.

However, a growing body of research over the past few years also cites blood vessel inflammation as a major independent risk factor for cardiovascular disease. University of Iowa researchers recently reported that very small amounts of endotoxin (a substance present in bacteria) cause blood vessel inflammation. Moreover, their findings suggest that drugs commonly prescribed to lower cholesterol may also reduce this inflammation, suggesting an additional beneficial effect of the cholesterol-lowering drugs known as statins.

"Increased awareness about cholesterol and lipoproteins really took off in the 1980s and 1990s, which was, and still is, a good thing," said Neal Weintraub, M.D., (left) associate professor of internal medicine and interim division director of cardiovascular diseases in the UI Roy J. and Lucille A. Carver College of Medicine, and a cardiovascular disease specialist at UI Hospitals and Clinics. "But over time it became obvious that many patients with cardiovascular disease have normal lipid levels. In fact, a significant percentage of patients with atherosclerosis have none of the other known conventional risk factors, such as smoking, hypertension and diabetes. Clearly there are other aspects involved, and research in the past few years has begun to identify inflammation as playing an important role."

Inflammation is a good thing in certain cases, such as signaling the body to send white blood cells to fight off infection and leading to the repair of cuts or wounds. However, long-term inflammation can wreak havoc on blood vessels, even if the inflammation is due to a relatively minor infection, said Lynn Stoll, Ph.D., an associate research scientist and member of Weintraub's research team.

"With chronic infections, like smoker's bronchitis or periodontitis (infection of the gums), small amounts of bacteria can intermittently get into the bloodstream where it doesn't belong," Stoll said. "Often these infections are just sort of smoldering - they're without major symptoms or are not severe enough to require treatment. But these types of infections can linger for months or years, causing inflammation that can, over the long term, potentially contribute to blood vessel blockage."

Blood vessel blockage of this sort probably doesn't occur from a single self-limited infection, such as a cut finger, Stoll noted. But chronic infections that produce mild elevations in blood endotoxin can potentially trigger activation of the body's immune system, thereby causing inflammation of blood vessels. Stoll, Weintraub and their colleagues recently reported that extremely low levels of endotoxin were found to cause inflammation in saphenous veins, the main blood vessels of the leg that are often used for grafting in coronary bypass surgery. The findings were published in the September 2003 issue of the journal Arteriosclerosis, Thrombosis and Vascular Biology. Stoll was co-lead author on the paper with Jim Rice, M.D., a cardiologist now in private practice in Springfield, Mo.

"Epidemiologic studies suggest that chronic subclinical infections associated with mild elevations in blood endotoxin - subtle infections that typically do not require antibiotics - may cause significant harm to the blood vessels and, as such, may constitute an independent risk factor for atherosclerosis," Weintraub said.

A key finding by the UI researchers was that atorvastatin, a cholesterol-lowering drug, part of a group of drugs known collectively as statins, blocked this inflammation.

"Statins have been prescribed for the past 15 to 20 years to help lower cholesterol," Stoll said. "However, over time it became clear that the effectiveness of statins in preventing cardiovascular disease was far greater than their effectiveness in simply lowering cholesterol. They also have a completely separate but very potent anti-inflammatory action."

Statins have been shown to be safe and effective in many large studies. Although side effects may occur, the benefit of statins far outweighs the risk for most patients, Weintraub noted. His research team is working to better understand the underlying cellular mechanisms that cause inflammation of blood vessels but, for the time being, it appears that statin drug therapy is extremely effective in alleviating vascular inflammation, he said.

So will testing for inflammation become as commonplace for doctors and patients as checking for cholesterol? A highly sensitive test for C-reactive protein (CRP), which is present in the bloodstream during episodes of inflammation, already exists. Just as there exists an established level for "normal" cholesterol, an ideal CRP level should be approximately 1 mg/L. A CRP level above approximately 2 mg/L indicates an increased risk for vascular disease.

"The test for CRP is already being incorporated into clinical practice," Weintraub said. "The clinical guidelines currently say to be selective in applying this, but I believe the guidelines will eventually be expanded. Studies show that treatment with statins can reduce cardiovascular events in patients who have normal cholesterol levels but who have elevated CRP levels. One could argue that this test should become, if not routine, very commonplace in patients who are determined to be at intermediate risk for development of cardiovascular disease. And that's a large segment of the population."

The UI team's research, funded by a grant from the National Institutes of Health (NIH), is a good example of research findings having an immediate impact on how care is delivered, Weintraub said.

Stoll added, "It's very important for the American public to better understand how their federal tax dollars are used by the NIH for research that can be of immediate benefit to them."

"We studied human blood vessels, the same vessels that are used for bypass surgery," Weintraub said. "Doctors know that there is a significant risk of bypass grafts themselves becoming occluded fairly soon after surgery. Our findings would suggest that taking statins even around the time of bypass surgery could protect the grafts from early occlusion. We haven't proven that yet, but it's one important question that arises from our work."

STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

MEDIA CONTACT: David Pedersen, 319-335-8032, david-pedersen@uiowa.edu.