Why do aneurysms form? New studies suggest leading role for white blood cells

July 13, 2005

ANN ARBOR, Mich. -- Each year, 200,000 Americans find out that the largest blood vessel in their body, the aorta, may burst open at any time. About 20,000 die suddenly from such a rupture. And another 36,000 have surgery to repair or replace the swelling section of aorta before time runs out.

But despite the deadly toll of this condition, called abdominal aortic aneurysm or AAA ("triple A"), experts know very little about why it happens. Now, a pair of papers from researchers at the University of Michigan Cardiovascular Center is shedding new light on the mystery.

In the July 12 issue of the journal Circulation, U-M researchers report that a certain type of white blood cell called a neutrophil appears to be crucial to AAA formation.

Neutrophils are the "first responders" of the body's immune system, appearing rapidly on the scene of an infection or injury to an area of tissue, and sounding the alarm to summon other immune cells to join the fight. They are key to the process of inflammation by which the body fights off insults from bacteria, viruses and injuries.

The two new papers show for the first time that neutrophils are important in the very early stages of AAA formation, when the aorta wall begins to weaken and bulge. The researchers think the cells may somehow act in combination with other AAA risk factors such as smoking, high blood pressure and inherited genetic vulnerability.

The U-M researchers made the findings in laboratory experiments on mice that had been treated to wipe out their neutrophils temporarily, and in rats that lacked the protein that lets neutrophils attach to tissue and start the "first aid" process. The researchers exposed a small part of the rodent aortas to a chemical that breaks down blood vessel tissue, then studied what happened in the rodents that had altered neutrophil systems and in comparison rodents that were normal.

In both cases, says senior author and U-M vascular surgeon Gilbert Upchurch, M.D., the rodents that had low neutrophil levels or no neutrophil-attaching protein developed little or no sign of aneurysm. Meanwhile, the injury to the aorta wall prompted the rapid formation of aneurysms in the normal rodents -- aneurysms that made the diameter of the blood vessel double or even quadruple.

In an accompanying editorial, Columbia University surgeon M. David Tilson, M.D., notes that the studies bring research on AAA formation and the role of the neutrophil to a new level and may lead to further discoveries that help sort out the AAA puzzle.

AAAs are an under-appreciated and under-researched public health threat, says Upchurch, who operates on dozens of AAA patients each year, including some whose aneurysms have already burst and who will die within minutes or hours if the bleeding isn't stopped. AAAs can go undetected for years; experts sometimes refer to them as a "ticking time bomb" inside a patient's abdomen.

In fact, an estimated 10 percent of all men over the age of 70 may have intact aortic aneurysms, which cause few symptoms except for occasional back pain or abdominal discomfort. If they are detected during this stage, for instance on a routine physical exam, X-Ray, MRI or CT scan, they can be repaired successfully 95 percent of the time.

Recently, new ideas about why aneurysms form have begun to take shape. "We're finding that in general, an aneurysm is an inadequate response to injury," Upchurch explains. "Something happens to damage elastin fibers in the blood vessel wall and, for some reason, the immune system's normal healing response doesn't work. Something eats away at smooth muscle cells in the wall of the aorta until it starts to fall apart."

Researchers have found that AAAs appear to be associated with high levels of enzymes that are capable of doing that eating. But the question of how those enzymes get there, and what prompts them to arrive, has been unanswered.

"Neutrophils are known to carry some of these enzymes, called matrix metalloproteinases and chemokines, which help them attack invaders," says Upchurch. "We wanted to see what the role of neutrophils was in the early stages of aneurysm formation and the progression of the aneurysm."

Upchurch and his colleagues performed one of the studies using mice that had been treated with an antibody that attacked their neutrophils and kept the levels of the cells circulating in the blood artificially low. They applied the enzyme elastase to the aortas of these mice and normal control mice. Two-thirds of the control mice developed an aneurysm at the injury site within two weeks, with an aneurysm area twice the normal size on average. In contrast, only 8 percent of the neutrophil-deficient mice developed an aneurysm and those that did develop were much smaller.

The researchers also looked at the levels, activity and production of enzymes before and during the aneurysm formation. For two of the matrix metalloproteinases, there was no difference between the two kinds of mice. For one called MMP-8, though, much less was produced in the neutrophil-deficient mice. But the researchers performed more experiments that showed that the lack of MMP-8 was not enough by itself to keep aneurysms from forming.

"Something else must be at work," says Upchurch, "and we're trying to find out what that is."

In the second study, the researchers looked at L-selectin, a protein on the surface of neutrophils that allow them to attach to tissue. They studied L-selectin production in the aortas of rats that had been injured with elastase or exposed to control conditions. They also studied mice that had been genetically altered by U-M researchers to lack the gene for L-selectin, and normal comparison mice.

In general, the rat aortas exposed to elastase had far higher levels of L-selectin in the days immediately after the injury. The L-selectin-deficient mice had significantly smaller aneurysms after elastase exposure, and only 38 percent of them developed aneurysms compared with 67 percent of the normal rats. Days after the injury, far fewer neutrophils and macrophage whit blood cells were present in the aorta walls of the rats that lacked L-selectin.

"Much further research is needed, but it's possible that a treatment based on L-selectin could be developed to prevent AAA development in high-risk patients," says Upchurch. "In addition to better screening and adequate monitoring of known AAAs, this kind of treatment is badly needed."

Upchurch and his colleagues performed the research in the Conrad Jobst Vascular Research Laboratories, part of the Section of Vascular Surgery in the U-M Medical School. They were funded by the National Institutes of Health, the Lifeline Foundation and the Jobst Vascular Research Fund. Upchurch is an associate professor of vascular surgery and the Leland Ira Doan Research Professor of Vascular Surgery at the U-M Medical School.
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In addition to Upchurch, the research teams included lead authors Jonathan Eliason, M.D., a former U-M vascular surgery resident now at Wilford Hall Medical Center at Lackland Air Force Base in San Antonio, TX; and Kevin Hannawa, B.S., a U-M medical student.

Other authors include U-M vascular surgeons Peter Henke, M.D., James Stanley, M.D., Thomas Wakefield, M.D., and Matthew Eagleton, M.D.; assistant professor of vascular surgery and animal research Daniel D. Myers, D.V.M.; chief U-M surgery resident Gorav Ailawadi, M.D. and surgery research resident Derek Woodrum, M.D., U-M research team members Charles Pearce, Karen Roelofs, D.V.M., John W. Ford, Michael Deogracias and Indranil Sinha; and former U-M surgery resident Vladimir Grigoryants, M.D. Two researchers from the Washington University School of Medicine's Section of Vascular Surgery, Robert W. Thompson, Ph.D. and Terri Ennis, are co-authors on the neutrophil depletion paper.

Reference: Circulation, Volume 112, Issue 2; July 12, 2005; pp. 232-240 and 241-247

For more information on AAA research and treatment at the U-M, visit vascular.um-surgery.org.

University of Michigan Health System

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